Use of substituted 2,3-dihydroimidazo[1,2-c]quinazolines for treating lymphomas

ABSTRACT

—use of a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or of a pharmaceutical composition containing same, as a sole active agent, or of a combination of a) said compound or a pharmaceutical composition containing said compound and b) one or more further active agents, for the preparation of a medicament for the treatment or prophylaxis of non-Hodgkin&#39;s lymphoma (NHL), particularly 1st line, 2nd line, relapsed, refractory, indolent or aggressive non-Hodgkin&#39;s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL); —combinations of a) said compound and b) one or more further active agents; —a pharmaceutical composition comprising said compound as a sole active agent for the treatment of non-Hodgkin&#39;s lymphoma (NHL), particularly 1st line, 2nd line, relapsed, refractory, indolent or aggressive non-Hodgkin&#39;s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL); —a pharmaceutical composition comprising a combination of a) said compound and b) one or more further active agents; —use of biomarkers involved in the modification of the expression of PI3K isoforms, BTK and IKK, BCR activation, BCR downstream activation of NFKB pathway, c-Myc, EZH2, for predicting the sensitivity and/or resistance of a cancer patient to said compound and providing a rationale-based synergistic combination as defined herein to increase sensitivity and/or to overcome resistance; and —a method of determining the level of a component of one or more of the expression of PI3K isoforms, BTK and IKK, BCR activation, BCR downstream activation of NFKB pathway, c-Myc, EZH2.

The present invention relates to:

-   -   use of a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or of a        pharmaceutical composition containing same, as a sole active        agent, or of a combination of a) said compound or a        pharmaceutical composition containing said compound and b) one        or more further active agents, for the preparation of a        medicament for the treatment or prophylaxis of non-Hodgkin's        lymphoma (hereinafter abbreviated to “NHL”), particularly 1st        line, 2nd line, relapsed, refractory, indolent or aggressive        non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma        (hereinafter abbreviated to “FL”), chronic lymphocytic leukaemia        (hereinafter abbreviated to “CLL”), marginal zone lymphoma        (hereinafter abbreviated to “MZL”), diffuse large B-cell        lymphoma (hereinafter abbreviated to “DLBCL”), mantle cell        lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to        “TL”), or peripheral T-cell lymphoma (hereinafter abbreviated to        “PTCL”); as a single agent or in combination with one or more        other active agents;    -   combinations of a) said compound and b) one or more further        active agents;    -   a pharmaceutical composition comprising said compound as a sole        active agent for the treatment of cancer;    -   a pharmaceutical composition comprising a combination of a) said        compound and b) one or more further active agents;    -   use of biomarkers, such as the expression of PI3K isoforms, BTK,        IKK, BCR activation, BCR downstream activation of NFκβ pathway,        c-Myc, EZH2, for predicting the sensitivity and/or resistance of        a cancer patient to said compound and providing a        rationale-based synergistic combination as defined herein to        increase sensitivity and/or to overcome resistance;        and    -   a method of determining the level of a component of one or more        of the expression of PI3K isoforms, BTK, IKK, BCR activation,        BCR downstream activation of NFκB pathway, c-Myc, EZH2.

BACKGROUND OF THE INVENTION

In recent decades the concept of developing anti-cancer medicationswhich target abnormally active protein kinases has led to a number ofsuccesses. In addition to the actions of protein kinases, lipid kinasesalso play an important role in generating critical regulatory secondmessengers. The PI3K family of lipid kinases generates3′-phosphoinositides that bind to and activate a variety of cellulartargets, initiating a wide range of signal transduction cascades(Vanhaesebroeck et al., 2001; Toker, 2002; Pendaries et al., 2003;Downes et al., 2005). These cascades ultimately induce changes inmultiple cellular processes, including cell proliferation, cellsurvival, differentiation, vesicle trafficking, migration, andchemotaxis.

PI3Ks can be divided into three distinct classes based upon differencesin both structure, and substrate preference. While members of the ClassII family of PI3Ks have been implicated in the regulation of tumorgrowth (Brown and Shepard, 2001; Traer et al., 2006), the bulk ofresearch has focused on the Class I enzymes and their role in cancer(Vivanco and Sawyers, 2002; Workman, 2004, Chen et al., 2005; Hennesseyet al., 2005; Stauffer et al., 2005; Stephens et al., 2005; Cully etal., 2006).

Class I PI3Ks have traditionally been divided into two distinctsub-classes based upon differences in protein subunit composition. TheClass I_(A) PI3Ks are comprised of a catalytic p110 catalytic subunit(p110α, p110β or p110γ) heterodimerized with a member of the p85regulatory subunit family. In contrast, the Class I_(B) PI3K catalyticsubunit (p110γ) heterodimerizes with a distinct p101 regulatory subunit(reviewed by Vanhaesebroeck and Waterfield, 1999; Funaki et al., 2000;Katso et al., 2001). The C-terminal region of these proteins contains acatalytic domain that possesses distant homology to protein kinases. ThePI3Kγ structure is similar to Class I_(A) p110s, but lacks theN-terminal p85 binding site (Domin and Waterfield, 1997). Though similarin overall structure, the homology between catalytic p110 subunits islow to moderate. The highest homology between the PI3K isoforms is inthe kinase pocket of the kinase domain.

The Class I PI3K isoforms associate with activated receptor tyrosinekinases (RTKs) (including PDGFR, EGFR, VEGFR, IGF1-R, c-KIT, CSF-R andMet), cytokine receptors, GPCRs, integrins, or with tyrosinephosphorylated adapter proteins (such as Grb2, Cbl, IRS-1 or Gab1), viatheir p85 regulatory subunits resulting in stimulation of the lipidkinase activity. Activation of the lipid kinase activity of the p110βand p110γ isoforms has been shown to occur in response to binding toactivated forms of the ras Oncogene (Kodaki et al, 1994). In fact, theoncogenic activity of these isoforms may require binding to ras (Kang etal., 2006). In contrast, the p110α and p110δ isoforms exhibit oncogenicactivity independent of ras binding, through constitutive activation ofAkt.

Class I PI3Ks catalyze the conversion of PI(4,5)P₂ [PIP₂] to PI(3,4,5)P₃[PIP₃]. The production of PIP₃ by PI3K affects multiple signalingprocesses that regulate and coordinate the biological end points of cellproliferation, cell survival, differentiation and cell migration. PIP₃is bound by Pleckstrin-Homology (PH) domain-containing proteins,including the phosphoinositide-dependent kinase, PDK1 and the Aktproto-oncogene product, localizing these proteins in regions of activesignal transduction and also contributing directly to their activation(Klippel et al., 1997; Fleming et al., 2000; Itoh and Takenawa, 2002;Lemmon, 2003). This co-localization of PDK1 with Akt facilitates thephosphorylation and activation of Akt. Carboxy-terminal phosphorylationof Akt on Ser⁴⁷³ promotes phosphorylation of Thr³⁰⁸ in the Aktactivation loop (Chan and Tsichlis, 2001; Hodgekinson et al., 2002;Scheid et al., 2002; Hresko et al., 2003). Once active, Aktphosphorylates and regulates multiple regulatory kinases of pathwaysthat directly influence cell cycle progression and cell survival.

Many of the effects of Akt activation are mediated via its negativeregulation of pathways which impact cell survival and which are commonlydysregulated in cancer. Akt promotes tumor cell survival by regulatingcomponents of the apoptotic and cell cycle machinery. Akt is one ofseveral kinases that phosphorylate and inactivate pro′ apoptotic BADproteins (del Paso et al., 1997; Pastorino et al., 1999). Akt may alsopromote cell survival through blocking cytochrome C-dependent caspaseactivation by phosphorylating Caspase 9 on Ser¹⁶⁶ (Cardone et al.,1998).

Akt impacts gene transcription on several levels. The Akt-mediatedphosphorylation of the MDM2 E3 ubiquitin ligase on Ser¹⁶⁶ and Ser¹⁸⁶facilitates the nuclear import of MDM2 and the formation and activationof the ubiquitin ligase complex. Nuclear MDM2 targets the p53 tumorsuppressor for degradation, a process that can be blocked by LY294002(Yap et al., 2000; Ogarawa et al., 2002). Downregulation of p53 by MDM2negatively impacts the transcription of p53-regulated pro-apoptoticgenes (e.g. Bax, Fas, PUMA and DR5), the cell cycle inhibitor,p21^(Cip1), and the PTEN tumor suppressor (Momand et al., 2000; Hupp etal., 2000; Mayo et al., 2002; Su et al., 2003). Similarly, theAkt-mediated phosphorylation of the Forkhead transcription factors FKHR,FKHRL and AFX (Kops et al., 1999; Tang et al., 1999), facilitates theirbinding to 14-3-3 proteins and export from the cell nucleus to thecytosol (Brunet et al., 1999). This functional inactivation of Forkheadactivity also impacts pro-apoptotic and pro-angiogenic genetranscription including the transcription of Fas ligand (Ciechomska etal., 2003) Bim, a pro-apoptotic Bcl-2 family member (Dijkers et al.,2000), and the Angiopoietin-1 (Ang-1) antagonist, Ang-2 (Daly et al.,2004). Forkhead transcription factors regulate the expression of thecyclin-dependent kinase (Cdk) inhibitor p27^(Kip1). Indeed, PI3Kinhibitors have been demonstrated to induce p27^(Kip1) expressionresulting in Cdk1 inhibition, cell cycle arrest and apoptosis (Dijkerset al., 2000). Akt is also reported to phosphorylate p21^(Cip1) onThr¹⁴⁵ and p27^(Kip1) on Thr¹⁵⁷ facilitating their association with14-3-3 proteins, resulting in nuclear export and cytoplasmic retention,preventing their inhibition of nuclear Cdks (Zhou et al., 2001; Motti etal., 2004; Sekimoto et al., 2004). In addition to these effects, Aktphosphorylates IKK (Romashkova and Makarov, 1999), leading to thephosphorylation and degradation of and subsequent nuclear translocationof NFκB, resulting in the expression of survival genes such as IAP andBcl-XL.

The PI3K/Akt pathway is also linked to the suppression of apoptosisthrough the JNK and p38^(MAPK) MAP Kinases that are associated with theinduction of apoptosis. Akt is postulated to suppress JNK and p38^(MAPK)signaling through the phosphorylation and inhibition of two JNK/p38regulatory kinases, Apoptosis Signal-regulating Kinase 1 (ASK1) (Kim etal., 2001: Liao and Hung, 2003; Yuan et al., 2003), and Mixed LineageKinase 3 (MLK3) (Lopez-llasaca et al., 1997; Barthwal et al., 2003;Figueroa et al., 2003). The induction of p38^(MAPK) activity is observedin tumors treated with cytotoxic agents and is required for those agentsto induce cell death (reviewed by Olson and Hallahan, 2004). Thus,inhibitors of the PI3K pathway may promote the activities ofco-administered cytotoxic drugs.

An additional role for PI3K/Akt signaling involves the regulation ofcell cycle progression through modulation of Glycogen Synthase Kinase 3(GSK3) activity. GSK3 activity is elevated in quiescent cells, where itphosphorylates cyclin D₁ on Ser²⁸⁶, targeting the protein forubiquitination and degradation (Diehl et al., 1998) and blocking entryinto S-phase. Akt inhibits GSK3 activity through phosphorylation on Ser⁹(Cross et al., 1995). This results in the elevation of Cyclin D₁ levelswhich promotes cell cycle progression. Inhibition of GSK3 activity alsoimpacts cell proliferation through activation of the wnt/beta-cateninsignaling pathway (Abbosh and Nephew, 2005; Naito et al., 2005; Wilkeret al., 2005; Kim et al., 2006; Segrelles et al., 2006). Akt mediatedphosphorylation of GSK3 results in stabilization and nuclearlocalization of the beta-catenin protein, which in turn leads toincreased expression of c-myc and cyclin D1, targets of thebeta-catenin/Tcf pathway.

Although PI3K signaling is utilized by many of the signal transductionnetworks associated with both oncogenes and tumor suppressors, PI3K andits activity have been linked directly to cancer. Overexpression of boththe p110α and p110β isoforms has been observed in bladder and colontumors and cell lines, and overexpression generally correlates withincreased PI3K activity (Benistant et al., 2000). Overexpression ofp110α has also been reported in ovarian and cervical tumors and tumorcell lines, as well as in squamous cell lung carcinomas. Theoverexpression of p110α in cervical and ovarian tumor lines isassociated with increased PI3K activity (Shayesteh et al., 1999; Ma etal., 2000). Elevated PI3K activity has been observed in colorectalcarcinomas (Phillips et al., 1998) and increased expression has beenobserved in breast carcinomas (Gershtein et al., 1999).

Over the last few years, somatic mutations in the gene encoding p110α(PIK3CA) have been identified in numerous cancers. The data collected todate suggests that PIK3CA is mutated in approximately 32% of colorectalcancers (Samuels et al., 2004; Ikenoue et al., 2005), 18-40% of breastcancers (Bachman et al., 2004; Campbell et al., 2004; Levine et al.,2005; Saal et al., 2005; Wu et al., 2005), 27% of glioblastomas (Samuelset al., 2004; Hartmann et al., 2005, Gallia et al., 2006), 25% ofgastric cancers (Byun et al., 2003; Samuels et al., 2004; Li et al.,2005), 36% of hepatocellular carcinomas (Lee et al., 2005), 4-12% ofovarian cancers (Levine et al., 2005; Wang et al., 2005), 4% of lungcancers (Samuels et al., 2004; Whyte and Holbeck, 2006), and up to 40%of endometrial cancers (Oda et al., 2005). PIK3CA mutations have beenreported in oligodendroma, astrocytoma, medulloblastoma, and thyroidtumors as well (Broderick et al., 2004; Garcia-Rostan et al., 2005).Based upon the observed high frequency of mutation, PIK3CA is one of thetwo most frequently mutated genes associated with cancer, the otherbeing K-ras. More than 80% of the PIK3CA mutations cluster within tworegions of the protein, the helical (E545K) and catalytic (H1047R)domains. Biochemical analysis and protein expression studies havedemonstrated that both mutations lead to increased constitutive p110αcatalytic activity and are in fact, oncogenic (Bader et al., 2006; Kanget al., 2005; Samuels et al., 2005; Samuels and Ericson, 2006).Recently, it has been reported that PIK3CA knockout mouse embryofibroblasts are deficient in signaling downstream from various growthfactor receptors (IGF-1, Insulin, PDGF, EGF), and are resistant totransformation by a variety of oncogenic RTKs (IGFR, wild-type EGFR andsomatic activating mutants of EGFR, Her2/Neu)(Zhao et al., 2006).

Functional studies of PI3K in vivo have demonstrated that siRNA-mediateddownregulation of p110P inhibits both Akt phosphorylation and HeLa celltumor growth in nude mice (Czauderna et al., 2003). In similarexperiments, siRNA-mediated downregulation of p110P was also shown toinhibit the growth of malignant glioma cells in vitro and in vivo (Pu etal., 2006). Inhibition of PI3K function by dominant-negative p85regulatory subunits can block mitogenesis and cell transformation (Huanget al., 1996; Rahimi et al., 1996). Several somatic mutations in thegenes encoding the p85α and p85β regulatory subunits of PI3K that resultin elevated lipid kinase activity have been identified in a number ofcancer cells as well (Janssen et al., 1998; Jimenez et al., 1998; Philpet al., 2001; Jucker et al., 2002; Shekar et al., 2005). NeutralizingPI3K antibodies also block mitogenesis and can induce apoptosis in vitro(Roche et al., 1994: Roche et al., 1998; Benistant et al., 2000). Invivo proof-of-principle studies using the PI3K inhibitors LY294002 andwortmannin, demonstrate that inhibition of PI3K signaling slows tumorgrowth in vivo (Powis et al., 1994; Shultz et al., 1995; Semba et al.,2002; Ihle et cll., 2004).

Overexpression of Class I PI3K activity, or stimulation of their lipidkinase activities, is associated with resistance to both targeted (suchas imatinib and tratsuzumab) and cytotoxic chemotherapeutic approaches,as well as radiation therapy (West et al., 2002; Gupta et al., 2003;Osaki et al., 2004; Nagata et al., 2004; Gottschalk et al., 2005; Kim etal., 2005). Activation of PI3K has also been shown to lead to expressionof multidrug resistant protein-1 (MRP-1) in prostate cancer cells andthe subsequent induction of resistance to chemotherapy (Lee et al.,2004).

The importance of PI3K signaling in tumorigenesis is further underscoredby the findings that the PTEN tumor suppressor, a PI(3)P phosphatase, isamong the most commonly inactivated genes in human cancers (Li et al.,1997, Steck et al., 1997; Ali et al., 1999; Ishii et al., 1999). PTENdephosphorylates PI(3,4,5)P₃ to PI(4,5)P₂ thereby antagonizingPI3K-dependent signaling. Cells containing functionally inactive PTENhave elevated levels of PIP₃, high levels of activity of PI3K signaling(Haas-Kogan et al., 1998; Myers et al., 1998; Taylor et al., 2000),increased proliferative potential, and decreased sensitivity topro-apoptotic stimuli (Stambolic et al., 1998). Reconstitution of afunctional PTEN suppresses PI3K signaling (Taylor et al., 2000),inhibits cell growth and re-sensitizes cells to pro-apoptotic stimuli(Myers et al., 1998; Zhao et al., 2004). Similarly, restoration of PTENfunction in tumors lacking functional PTEN inhibits tumor growth in vivo(Stahl et al., 2003; Su et al., 2003; Tanaka and Grossman, 2003) andsensitizes cells to cytotoxic agents (Tanaka and Grossman, 2003).

The class I family of PI3Ks clearly plays an important role in theregulation of multiple signal transduction pathways that promote cellsurvival and cell proliferation, and activation of their lipid kinaseactivity contributes significantly to the development of humanmalignancies. Furthermore, inhibition of PI3K may potentially circumventthe cellular mechanisms that underlie resistance to chemotherapeuticagents. A potent inhibitor of Class I PI3K activities would thereforehave the potential not only to inhibit tumor growth but to alsosensitize tumor cells to pro-apoptotic stimuli in vivo.

Signal transduction pathways originating from chemoattractant receptorsare considered to be important targets in controlling leukocyte motilityin inflammatory diseases. Leukocyte trafficking is controlled bychemoattractant factors that activate heterotrimeric GPCRs and therebytrigger a variety of downstream intracellular events. Signaltransduction along one of these pathways that results in mobilization offree Ca²⁺, cytoskelatal reorganization, and directional movement dependson lipid-dervied second messengers producted by PI3K activity (Wymann etal., 2000; Stein and Waterfield, 2000).

PI3Kγ modulates baseline cAMP levels and controls contractility incells. Recent research indicates that alterations in baseline cAMPlevels contribute to the increased contractility in mutant mice. Thisresearch, therefore, shows that PI3Kγ inhibitors afford potentialtreatments for congestive heart failure, ischemia, pulmonaryhypertension, renal failure, cardiac hypertrophy, atherosclerosis,thromboembolism, and diabetes.

PI3K inhibitors would be expected to block signal transduction fromGPCRs and block the activation of various immune cells, leading to abroad anti-inflammatory profile with potential for the treatment ofinflammatory and immunoregulatory diseases, including asthma, atopicdermatitis, rhinitis, allergic diseases, chronic obstructive pulmonarydisease (COPD), septic shock, joint diseases, autoimmune pathologiessuch as rheumatoid arthritis and Graves' disease, diabetes, cancer,myocardial contractility disorders, thromboembolism, andatherosclerosis.

Activation of the PI3K/AKT pathway by B-cell receptor signaling and itsrole in the pathogenesis of non-Hodgkin's lymphoma (NHL) have beenhighlighted in a number of studies. However, the relative importance ofphosphoinositide 3-kinase (PI3K) isoforms and other downstream kinases,e.g. Bruton's tyrosine kinase (BTK) and IκB kinase (IKK), fortherapeutic application in NHL has not been fully addressed. To answerthis question, we selected and characterized a panel of cell linesrepresenting frequent mutations CD79, MyD88, CARD11, Bcl2, c-Myc, orEZH2 in diffuse large B-cell lymphoma (DLBCL), a major type ofaggressive NHL. Analyzing the expression of PI3K isoforms indicated thatnot only PI3Kδ, an isoform known to be enriched in lymphocytes, but alsoother 3 PI3K isoforms are highly expressed. Sensitivity profiling of thepan-PI3K inhibitor COMPOUND A (with potent activity against PI3Kα[IC₅₀=0.5 nM] and PI3Kδ [IC₅₀=0.7 nM]), the PI3Kδ-selective inhibitorGS-1101, the irreversible BTK inhibitor ibrutinib (PCI-32765), and theIKKβ inhibitor BAY compound B revealed that the pan-PI3K inhibitorCOMPOUND A has a broader antitumor spectrum and is more effective thaninhibition of PI3Kδ or BTK only. Further analysis of oncogenic signalingpathways discovered feedback activation of ERK by PI3Kδ- orBTK-selective inhibition, and re-activation of IKK by IKKβ inhibition.Combination of PI3K inhibitor COMPOUND A with BTK or IKK inhibitorsshowed synergistic antitumor effects in a subset of tumor cell lines,indicating the heterogeneity of DLBCL and that a biomarker might benecessary for successfully developing COMPOUND A-based therapeutics inaggressive NHL. Taken together, these findings provide further insightsinto the mechanism of action of PI3K inhibitor COMPOUND A and supportongoing Phase II clinical studies in NHL patients

Follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) are 2 ofthe most common non-Hodgkin's lymphomas (NHLs) worldwide. There remainsa high unmet medical need for effective therapeutics for refractory andrelapsed follicular lymphoma and DLBCL.

The critical role of phosphoinositide 3-kinase (PI3K)δ in regulatingdownstream events of the B-cell receptor (BCR) has been evident by theclinical benefit of GS-1101, a PI3Kδ-selective inhibitor in follicularlymphoma patients.

Several lines of evidence suggested that a pan-PI3K inhibitor mayproduce a better therapeutic benefit compared with PI3Kδ-selectiveinhibition.

In PI3Kδ knockout mice, PI3Kα was shown to compensate tonic signaling, acharacteristic of many B-cell malignancies (see reference 1A).

-   -   8% of DLBCL patients have a PIK3CA mutation and 37% have reduced        PTEN expression or loss of function of PTEN.    -   In the clinic, p110α-mediated constitutive PI3K signaling        appeared to limit the efficacy of p110δ-selective inhibition in        mantle cell lymphoma (see reference 2A).    -   Although the PI3Kδ-selective inhibitor GS-1101 demonstrated        promising clinical response in indolent NHL, so far no efficacy        has been shown in aggressive NHL, eg DLBCL.    -   COMPOUND A is a pan-PI3K inhibitor potently inhibiting PI3Kα and        PI3Kδ, with IC₅₀ values of 0.5 and 0.7 nM, respectively (see        reference 3A).    -   In this study, we investigated the effects and the mechanism of        action of inhibiting key molecular targets in NHL cells using        the pan-PI3K inhibitor COMPOUND A, PI3Kδ-selective inhibitor        GS-1101, Bruton's tyrosine kinase (BTK) inhibitor ibrutinib        (PCI-32765), and an IκB kinase (IKK) inhibitor BAY compound B        (see reference 4A) as single agents.    -   Based on the mechanism of action, the present patent application        relates to and covers rational combination therapies for        effective treatment of aggressive NHL.

The present invention is thus to identify molecular markers predictingthe sensitivity and/or resistance of the cancer patients toward the PI3Kinhibitors described herein. Furthermore, the present invention alsorelates to the identification of resistance mechanisms and thereforeprovides a rationale-based synergistic combination to overcome theresistance.

To the Applicant's knowledge, no specific disclosure in the prior art isknown that 2,3-dihydroimidazo[1,2-c]quinazoline compounds would beeffective in the treatment or prophylaxis of non-Hodgkin's lymphoma(NHL), particularly 1st line, 2nd line, relapsed, refractory, indolentor aggressive non-Hodgkin's lymphoma (NHL), in particular follicularlymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zonelymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle celllymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma(PTCL).

It has been found, and this is the basis of the present invention, that2,3-dihydroimidazo[1,2-c]quinazoline compounds, as described and definedherein, show a beneficial effect in the treatment or prophylaxis ofnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL).

Thus, in accordance with a first aspect, the present invention relatesto the use of 2,3-dihydroimidazo[1,2-c]quinazoline compounds, or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof, as a sole active agent, or of pharmaceutical compositionscontaining such compounds or a physiologically acceptable salt, solvate,hydrate or stereoisomer thereof, for the preparation of a medicament forthe treatment or prophylaxis of non-Hodgkin's lymphoma (NHL),particularly 1st line, 2nd line, relapsed, refractory, indolent oraggressive non-Hodgkin's lymphoma (NHL), in particular follicularlymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zonelymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle celllymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma(PTCL).

In accordance with a second aspect, the present invention relates tocombinations of:

a) a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a physiologicallyacceptable salt, solvate, hydrate or stereoisomer thereof; andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of: PI3Kδ-selective inhibitor GS-1101, BTKinhibitor ibrutinib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY86-9766 (RDEA-119)).

In accordance with a third aspect, the present invention relates topharmaceutical compositions comprising a2,3-dihydroimidazo[1,2-c]quinazoline compound, or a physiologicallyacceptable salt, solvate, hydrate or stereoisomer thereof, as a soleactive agent, for the treatment of non-Hodgkin's lymphoma (NHL),particularly 1st line, 2nd line, relapsed, refractory, indolent oraggressive non-Hodgkin's lymphoma (NHL), in particular follicularlymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zonelymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle celllymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma(PTCL).

In accordance with a fourth aspect, the present invention relates topharmaceutical compositions comprising a combination of:

a) a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a physiologicallyacceptable salt, solvate, hydrate or stereoisomer thereof; andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of: PI3Kδ-selective inhibitor GS-1101, BTKinhibitor ibrutinib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY86-9766 (RDEA-119)).

In accordance with a fifth aspect, the present invention relates to theuse of combinations of:

a) a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a physiologicallyacceptable salt, solvate, hydrate or stereoisomer thereof;or of a pharmaceutical composition containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof,andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of: PI3Kδ-selective inhibitor GS-1101, BTKinhibitor ibrutinib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY86-9766 (RDEA-119));for the preparation of a medicament for the treatment or prophylaxis ofnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL).

In accordance with a sixth aspect, the present invention relates to useof biomarkers involved in the modification of target expression, BCRactivation, BCR downstream activation of NFκB pathway, c-Myc, EZH2, forpredicting the sensitivity and/or resistance of a patient withnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL), to a2,3-dihydroimidazo[1,2-c]quinazoline compound as defined herein, thusproviding a rationale-based synergistic combination as defined herein toovercome the resistance (patient stratification).

In accordance with a seventh aspect, the present invention relates to amethod of determining the level of a component of one or more of theexpression of PI3K isoforms, BTK, IKK, BCR activation, BCR downstreamactivation of NFκB pathway, c-Myc, EZH2.

In accordance a particular embodiment of any of the above aspects of thepresent invention, said cancer is non-Hodgkin's lymphoma (NHL),particularly 1st line, 2nd line, relapsed, refractory, indolent oraggressive non-Hodgkin's lymphoma (NHL).

In accordance a particular embodiment of any of the above aspects of thepresent invention, said cancer is follicular lymphoma (FL).

In accordance a particular embodiment of any of the above aspects of thepresent invention, said cancer is chronic lymphocytic leukaemia (CLL).

In accordance a particular embodiment of any of the above aspects of thepresent invention, said cancer is marginal zone lymphoma (MZL).

In accordance a particular embodiment of any of the above aspects of thepresent invention, said cancer is diffuse large B-cell lymphoma (DLBCL).

In accordance a particular embodiment of any of the above aspects of thepresent invention, said cancer is mantle cell lymphoma (MCL).

In accordance a particular embodiment of any of the above aspects of thepresent invention, said cancer is transformed lymphoma (TL).

In accordance a particular embodiment of any of the above aspects of thepresent invention, said cancer is peripheral T-cell lymphoma (PTCL).

DETAILED DESCRIPTION OF THE INVENTION

A first aspect of the present invention relates to the use of a compoundof general formula (A):

in which:X represents CR⁵R⁶ or NH;Y¹ represents CR³ or N;the chemical bond between

represents a single bond or double bond,with the proviso that when the

represents a double bond, Y² and Y³ independently represent CR⁴ or N,and when

represents a single bond, Y² and Y³ independently represent CR³R⁴ orNR⁴;Z¹, Z², Z³ and Z⁴ independently represent CH, CR² or N;

-   -   R¹ represents aryl optionally having 1 to 3 substituents        selected from R¹¹, C₃₋₈ cycloalkyl optionally having 1 to 3        substituents selected from R¹¹, C₁₋₆ alkyl optionally        substituted by aryl, heteroaryl, C₁₋₆ alkoxyaryl, aryloxy,        heteroaryloxy or one or more halogen,        -   C₁₋₆ alkoxy optionally substituted by carboxy, aryl,            heteroaryl, C₁₋₆ alkoxyaryl, aryloxy, heteroaryloxy or one            or more halogen, or        -   a 3 to 15 membered mono- or bi-cyclic heterocyclic ring that            is saturated or unsaturated, optionally having 1 to 3            substituents selected from R¹¹, and contains 1 to 3            heteroatoms selected from the group consisting of N, O and            S,        -   wherein        -   R¹¹ represents halogen, nitro, hydroxy, cyano, carboxy,            amino, N—(C₁₋₆alkyl)amino, N-(hydroxyC₁₋₆alkyl)amino,            N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆acyl)amino,            N-(formyl)-N—(C₁₋₆alkyl)amino, N—(C₁₋₆alkanesulfonyl)amino,            N-(carboxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino,            N—(C₁₋₆alkoxycabonyl)amino, N-[N,N-di(C₁₋₆alkyl)amino            methylene]amino, N-[N,N-di(C₁₋₆alkyl)amino            (C₁₋₆alkyl)methylene]amino, N-[N,N-di(C₁₋₆alkyl)amino            C₂₋₆alkenyl]amino, aminocarbonyl,            N—(C₁₋₆alkyl)aminocarbonyl, N,N-di(C₁₋₆alkyl)aminocarbonyl,            C₃₋₈cycloalkyl, C₁₋₆, alkylthio, C₁₋₆alkanesulfonyl,            sulfamoyl, C₁₋₆alkoxycarbonyl, N-arylamino wherein said aryl            moiety is optionally having 1 to 3 substituents selected            from R¹⁰¹, N-(aryl C₁₋₆alkyl)amino wherein said aryl moiety            is optionally having 1 to 3 substituents selected from R¹⁰¹,            aryl C₁₋₆alkoxycarbonyl wherein said aryl moiety is            optionally having 1 to 3 substituents selected from R¹⁰¹,        -   C₁₋₆ alkyl optionally substituted by mono-, di- or            tri-halogen, amino, N—(C₁₋₆ alkyl)amino or N,N-di(C₁₋₆            alkyl)amino,        -   C₁₋₆ alkoxy optionally substituted by mono-, di- or            tri-halogen, N—(C₁₋₆ alkyl)sulfonamide, or            N-(aryl)sulfonamide,        -   or        -   a 5 to 7 membered saturated or unsaturated ring having 1 to            3 heteroatoms selected from the group consisting of O, S and            N, and optionally having 1 to 3 substituents selected from            R¹⁰¹        -   wherein        -   R¹⁰¹ represents halogen, carboxy, amino, N—(C₁₋₆            alkyl)amino, N,N-di(C₁₋₆alkyl)amino, aminocarbonyl,            N—(C₂₋₆alkyl)aminocarbonyl, N,N-di(C₁₋₆alkyl)aminocarbonyl,            pyridyl,            -   C₁₋₆ alkyl optionally substituted by cyano or mono- di-                or tri-halogen,            -   and            -   C₁₋₆ alkoxy optionally substituted by cyano, carboxy,                amino, N—(C₁₋₆ alkyl)amino, N,N-di(C₂₋₆alkyl)amino,                aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl,                N,N-di(C₂₋₆alkyl)aminocarbonyl or mono-, di- or                tri-halogen;    -   R² represents hydroxy, halogen, nitro, cyano, amino,        N—(C₂₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,        N-(hydroxyC₁₋₆alkyl)amino,        N-(hydroxyC₂₋₆alkyl)-N—(C₂₋₆alkyl)amino, C₁₋₆ acyloxy, aminoC₂₋₆        acyloxy, C₂₋₆alkenyl, aryl,        -   a 5-7 membered saturated or unsaturated heterocyclic ring            having 1 to 3 heteroatoms selected from the group consisting            O, S and N, and optionally substituted by        -   hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, oxo, amino, amino C₁₋₆            alkyl, N—(C₁₋₆ alkyl)amino, N,N-di(C₁₋₆ alkyl)amino, N—(C₁₋₆            acyl)amino, N—(C₁₋₆ alkyl)carbonylamino, phenyl, phenyl C₁₋₆            alkyl, carboxy, C₁₋₆alkoxycarbonyl, aminocarbonyl, N—(C₁₋₆            alkyl)aminocarbonyl, or N,N-di(C₁₋₆ alkyl)amino, —C(O)—R²⁰        -   wherein        -   R²⁰ represents C₁₋₆ alkyl, C₁₋₆ alkoxy, amino, N—(C₁₋₆            alkyl)amino, N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino, or            a 5-7 membered saturated or unsaturated heterocyclic ring            having 1 to 3 heteroatoms selected from the group consisting            O, S and N, and optionally substituted by C₁₋₆ alkyl, C₁₋₆            alkoxy, oxo, amino, N—(C₁₋₆alkyl)amino,            N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino, phenyl, or            benzyl,            -   C₁₋₆ alkyl optionally substituted by R²¹,            -   or            -   C₁₋₆ alkoxy optionally substituted by R²¹,            -   wherein            -   R²¹ represents cyano, mono-, di or tri-halogen, hydroxy,                amino, N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,                N-(hydroxyC₁₋₆ alkyl)amino, N-(halophenylC₁₋₆                alkyl)amino, amino C₂₋₆ alkylenyl, C₁₋₆ alkoxy,                hydroxyC₁₋₆ alkoxy, —C(O)—R²⁰¹, —NHC(O)—R²⁰¹,                C₃₋₈cycloalkyl, isoindolino, phthalimidyl,                2-oxo-1,3-oxazolidinyl, aryl or a 5 or 6 membered                saturated or unsaturated heterocyclic ring having 1 to 4                heteroatoms selected from the group consisting O, S and                N, and optionally substituted by hydroxy, C₁₋₆ alkyl,                C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, hydroxyC₁₋₆ alkoxy,                oxo, amino, aminoC₁₋₆alkyl, N—(C₁₋₆alkyl)amino,                N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino, or benzyl,                -   wherein                -   R²⁰¹ represents hydroxy, amino, N—(C₁₋₆ alkyl)amino,                    N,N-di(C₁₋₆ alkyl)amino, N-(halophenylC₁₋₆                    alkyl)amino, C₁₋₆ alkyl, aminoC₁₋₆ alkyl, aminoC₂₋₆                    alkylenyl, C₁₋₆ alkoxy, a 5 or 6 membered saturated                    or unsaturated heterocyclic ring having 1 to 4                    heteroatoms selected from the group consisting O, S                    and N, and optionally substituted by hydroxy, C₁₋₆                    alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, hydroxyC₁₋₆                    alkoxy, oxo, amino, N—(C₁₋₆alkyl)amino,                    N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆acyl)amino or benzyl;    -   R³ represents hydrogen, halogen, aminocarbonyl, or C₁₋₆ alkyl        optionally substituted by aryl C₁₋₆ alkoxy or mono-, di- or        tri-halogen;    -   R⁴ represents hydrogen or C₁₋₆ alkyl;    -   R⁵ represents hydrogen or C₁₋₆ alkyl; and    -   R⁶ represents halogen, hydrogen or C₁₋₆ alkyl,        or a physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof, as a sole active agent,        or of combinations of:        a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a        physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof; and        b) one or more further active agents, in particular an active        agent selected from an anti-angiogenesis,        anti-hyper-proliferative, antiinflammatory, analgesic,        immunoregulatory, diuretic, antiarrhytmic,        anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or        antiviral agent, more particularly one or more further active        agents selected from the group consisting of: PI3Kδ-selective        inhibitor GS-1101, BTK inhibitor ibrutinib, IKK inhibitor BAY        Compound B, and REFAMETINIB (BAY 86-9766 (RDEA-119));        or of pharmaceutical compositions containing such compounds or a        physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof,        or of pharmaceutical compositions containing such combinations,        for the preparation of a medicament for the treatment or        prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st        line, 2nd line, relapsed, refractory, indolent or aggressive        non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma        (FL), chronic lymphocytic leukaemia (CLL), marginal zone        lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle        cell lymphoma (MCL), transformed lymphoma (TL), or peripheral        T-cell lymphoma (PTCL).

In a particular embodiment of the above-mentioned first aspect, thepresent invention relates to the use of a compound selected from thefollowing list,

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, as a sole active agent,or of combinations of:a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof; andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of: PI3Kδ-selective inhibitor GS-1101, BTKinhibitor ibrutinib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY86-9766 (RDEA-119));or of pharmaceutical compositions containing such compounds or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof,or of pharmaceutical compositions containing such combinationsfor the preparation of a medicament for the treatment or prophylaxis ofnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL):

-   N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   2-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-pyridin-3-ylethylenol;-   N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;-   6-(acetamido)-N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-{5-[2-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-hydroxyyinyl]pyridin-2-yl}acetamide;-   2-({5-[2-hydroxy-2-pyridin-3-ylyinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)-N,N-dimethylacetamide;-   2-[7-methoxy-8-(tetrahydro-2H-pyran-2-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol;-   2-[8-(2-hydroxyethoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol;-   ({5-[2-hydroxy-2-pyridin-3-ylyinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)acetic    acid;-   4-({5-[2-hydroxy-2-pyridin-3-ylyinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)butanoic    acid;-   ({5-[2-hydroxy-2-pyridin-3-ylyinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)acetonitrile;-   2-[7-methoxy-8-(2H-tetrazol-5-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol;-   2-[7-methoxy-8-(4-morpholin-4-yl-4-oxobutoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol;-   5-[1-hydroxy-2-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)yinyl]pyridin-3-ol;-   N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-hydroxynicotinamide;-   6-(acetamido)-N-(7,9-dimethoxy-8-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-hydroxynicotinamide;-   5-hydroxy-N-(7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-[(4-methoxybenzyl)oxy]nicotinamide;-   N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-hydroxynicotinamide;-   5-hydroxy-N-[8-(trifluoromethyl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-{8-[3-(1,3-dioxo-1,3-dihydro-2H-isoindo1-2-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-(7-bromo-8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   6-amino-N-(8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   1-(1H-benzimidazol-5-yl)-2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)ethylenol;-   2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-(2,4-dimethyl-1,3-thiazol-5-yl)ethylenol;-   N-(9-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;-   N-(8-bromo-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-(8-bromo-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;-   N-(8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;-   N-(8-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;-   N-[8-(trifluoromethyl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1H-benzimidazole-5-carboxamide;-   N-(7-fluoro-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;-   N-(7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-(8-chloro-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;-   6-(acetamido)-N-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   1-(1H-benzimidazol-5-yl)-2-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)ethylenol;-   N-{5-[1-hydroxy-2-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)vinyl]pyridin-2-yl}acetamide;-   6-methyl-N-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   1-(1H-benzimidazol-5-yl)-2-[8-(4-methylpiperazin-1-yl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]ethylenol;-   N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-3H-imidazo[4,5-b]pyridine-6-carboxamide;-   N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-3H-imidazo[4,5-b]pyridine-6-carboxamide;-   N-[7-(trifluoromethyl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1H-benzimidazole-5-carboxamide;-   N-(7,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;-   N-{5-[2-(7,9-dimethoxy-8-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-hydroxyvinyl]pyridin-2-yl}acetamide;-   N-{5-[2-(7-bromo-9-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-hydroxyvinyl]pyridin-2-yl}acetamide;    and-   2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-pyridin-3-ylethylenol;

Another embodiment of the present invention encompasses the use of acompound having the formula (I):

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, in which:

-   R¹ represents —(CH₂)_(n)—(CHR⁴)—(CHN—N(R⁵)(R^(5′));-   R² represents a heteroaryl optionally substituted with 1, 2 or 3 R⁶    groups;-   R³ represents alkyl or cycloalkyl;-   R⁴ represents hydrogen, hydroxy or alkoxy; and-   R⁵ and R^(5′) may be the same or different and represent    independently, hydrogen, alkyl, cycloalkylalklyl, or alkoxyalkyl or    R⁵ and R^(5′) may be taken together with the nitrogen atom to which    they are bound to form a 3-7 membered nitrogen containing    heterocyclic ring optionally containing at least one additional    heteroatom selected from oxygen, nitrogen or sulfur and which may be    optionally substituted with 1 or more R^(6′) groups, or R⁴ and R⁵    may be taken together with the atoms to which they are bound to form    a 5-6 membered nitrogen containing heterocyclic ring optionally    containing 1 or more nitrogen, oxygen or sulfur atoms and which may    be optionally substituted with 1 or more R^(6′) groups;    each occurrence of R⁶ may be the same or different and is    independently halogen, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkylalklyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,    heterocyclic ring, heterocyclylalkyl, alkyl-OR⁷, alkyl-SW,    alkyl-N(R²)(R²), alkyl-COR², —CN, —COOR⁷, —CON(R⁷)(R^(7′)), —OR⁷,    —SR⁷, —N(R⁷)(R^(7′)), or NR⁷COR⁷ each of which may be optionally    substituted with 1 or more Fe groups;    each occurrence of R^(6′) may be the same or different and is    independently alkyl, cycloalkylalklyl, or alkyl-OR⁷;    each occurrence of R² and R^(7′) may be the same or different and is    independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl, heteroaryl,    heterocyclic ring, heterocyclylalkyl, or heteroarylalkyl;    each occurrence of R⁸ is independently nitro, hydroxy, cyano,    formyl, acetyl, halogen, amino, alkyl, alkoxy, alkenyl, alkynyl,    cycloalkyl, cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl,    heteroaryl, heterocyclic ring, heterocyclylalkyl, or    heteroarylalkyl;    n is an integer from 1-4 and m is an integer from 0-4 with the    proviso that when R⁴ and R⁵ are taken together with the atoms to    which they are bound to form a 5-6 membered nitrogen containing    ring, n+m≦4;    or a physiologically acceptable salt, solvate, hydrate or    stereoisomer thereof, as a sole active agent,    or of combinations of:    a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a    physiologically acceptable salt, solvate, hydrate or stereoisomer    thereof; and    b) one or more further active agents, in particular an active agent    selected from an anti-angiogenesis, anti-hyper-proliferative,    antiinflammatory, analgesic, immunoregulatory, diuretic,    antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia,    anti-diabetic or antiviral agent, more particularly one or more    further active agents selected from the group consisting of:    PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK    inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766 (RDEA-119));    or of pharmaceutical compositions containing such compounds or a    physiologically acceptable salt, solvate, hydrate or stereoisomer    thereof,    or of pharmaceutical compositions containing such combinations,    for the preparation of a medicament for the treatment or prophylaxis    of non-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line,    relapsed, refractory, indolent or aggressive non-Hodgkin's lymphoma    (NHL), in particular follicular lymphoma (FL), chronic lymphocytic    leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell    lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma    (TL), or peripheral T-cell lymphoma (PTCL).

In a preferred embodiment, the invention encompasses the use of acompound of Formula (I), wherein R² is a nitrogen containing heteroaryloptionally substituted with 1, 2 or 3 R⁶ groups,

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, as a sole active agent,or of combinations of:a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof; andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of:

-   -   PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK        inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766        (RDEA-119));        or of pharmaceutical compositions containing such compounds or a        physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof,        or of pharmaceutical compositions containing such combinations,        for the preparation of a medicament for the treatment or        prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st        line, 2nd line, relapsed, refractory, indolent or aggressive        non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma        (FL), chronic lymphocytic leukaemia (CLL), marginal zone        lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle        cell lymphoma (MCL), transformed lymphoma (TL), or peripheral        T-cell lymphoma (PTCL).

In another preferred embodiment, the invention encompasses the use of acompound of Formula (I), wherein R⁵ and R^(5′) are independently alkyl,

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, as a sole active agent,or of combinations of:a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof; andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of:

-   -   PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK        inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766        (RDEA-119));        or of pharmaceutical compositions containing such compounds or a        physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof,        or of pharmaceutical compositions containing such combinations,        for the preparation of a medicament for the treatment or        prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st        line, 2nd line, relapsed, refractory, indolent or aggressive        non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma        (FL), chronic lymphocytic leukaemia (CLL), marginal zone        lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle        cell lymphoma (MCL), transformed lymphoma (TL), or peripheral        T-cell lymphoma (PTCL).

In still another preferred embodiment, the invention encompasses the useof a compound of Formula (I), wherein R⁵ and R^(5′) are taken togetherwith the nitrogen atom to which they are bound to form a 5-6 memberednitrogen containing heterocyclic ring containing at least one additionalheteroatom selected from oxygen, nitrogen or sulfur and which may beoptionally substituted with 1 or more R^(6′) groups,

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, as a sole active agent,or of combinations of:a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof; andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of:

-   -   PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK        inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766        (RDEA-119));        or of pharmaceutical compositions containing such compounds or a        physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof,        or of pharmaceutical compositions containing such combinations,        for the preparation of a medicament for the treatment or        prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st        line, 2nd line, relapsed, refractory, indolent or aggressive        non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma        (FL), chronic lymphocytic leukaemia (CLL), marginal zone        lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle        cell lymphoma (MCL), transformed lymphoma (TL), or peripheral        T-cell lymphoma (PTCL).

In yet another preferred embodiment, the invention encompasses the useof a compound of Formula (I), wherein Fe is hydroxyl,

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, as a sole active agent,or of combinations of:a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof; andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of:

-   -   PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK        inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766        (RDEA-119));        or of pharmaceutical compositions containing such compounds or a        physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof,        or of pharmaceutical compositions containing such combinations,        for the preparation of a medicament for the treatment or        prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st        line, 2nd line, relapsed, refractory, indolent or aggressive        non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma        (FL), chronic lymphocytic leukaemia (CLL), marginal zone        lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle        cell lymphoma (MCL), transformed lymphoma (TL), or peripheral        T-cell lymphoma (PTCL).

In another preferred embodiment, the invention encompasses the use of acompound of Formula (I), wherein Fe and R⁵ are taken together with theatoms to which they are bound to form a 5-6 membered nitrogen containingheterocyclic ring optionally containing 1 or more nitrogen, oxygen orsulfur atoms and which may be optionally substituted with 1 or more R⁶groups,

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, as a sole active agent,or of combinations of:a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof; andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of:

-   -   PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK        inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766        (RDEA-119));        or of pharmaceutical compositions containing such compounds or a        physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof,        or of pharmaceutical compositions containing such combinations,        for the preparation of a medicament for the treatment or        prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st        line, 2nd line, relapsed, refractory, indolent or aggressive        non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma        (FL), chronic lymphocytic leukaemia (CLL), marginal zone        lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle        cell lymphoma (MCL), transformed lymphoma (TL), or peripheral        T-cell lymphoma (PTCL).

In yet another preferred embodiment, the invention encompasses the useof a compound of Formula (I), wherein R³ is methyl,

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, as a sole active agent,or of combinations of:a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof; andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of:

-   -   PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK        inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766        (RDEA-119));        or of pharmaceutical compositions containing such compounds or a        physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof,        or of pharmaceutical compositions containing such combinations,        for the preparation of a medicament for the treatment or        prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st        line, 2nd line, relapsed, refractory, indolent or aggressive        non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma        (FL), chronic lymphocytic leukaemia (CLL), marginal zone        lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle        cell lymphoma (MCL), transformed lymphoma (TL), or peripheral        T-cell lymphoma (PTCL).

In still another preferred embodiment, the invention encompasses the useof a compound of Formula (I), wherein R² is pyridine, pyridazine,pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan or thiophene,optionally substituted with 1, 2 or 3 R⁶ groups; more preferablypyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole,optionally substituted with 1, 2 or 3 R⁶ groups,

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, as a sole active agent,or of combinations of:a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof; andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of:

-   -   PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK        inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766        (RDEA-119));        or of pharmaceutical compositions containing such compounds or a        physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof,        or of pharmaceutical compositions containing such combinations,        for the preparation of a medicament for the treatment or        prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st        line, 2nd line, relapsed, refractory, indolent or aggressive        non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma        (FL), chronic lymphocytic leukaemia (CLL), marginal zone        lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle        cell lymphoma (MCL), transformed lymphoma (TL), or peripheral        T-cell lymphoma (PTCL).

In a distinct embodiment, the invention encompasses the use of acompound of formula (Ia)

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, wherein R² is as defined above,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, as a sole active agent,or of combinations of:a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof; andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of:

-   -   PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK        inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766        (RDEA-119));        or of pharmaceutical compositions containing such compounds or a        physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof,        or of pharmaceutical compositions containing such combinations,        for the preparation of a medicament for the treatment or        prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st        line, 2nd line, relapsed, refractory, indolent or aggressive        non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma        (FL), chronic lymphocytic leukaemia (CLL), marginal zone        lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle        cell lymphoma (MCL), transformed lymphoma (TL), or peripheral        T-cell lymphoma (PTCL).

In another distinct embodiment, the invention encompasses the use of acompound of formula (Ib):

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, wherein R² is as defined above,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, as a sole active agent,or of combinations of:a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof; andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of:

-   -   PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK        inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766        (RDEA-119));        or of pharmaceutical compositions containing such compounds or a        physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof,        or of pharmaceutical compositions containing such combinations,        for the preparation of a medicament for the treatment or        prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st        line, 2nd line, relapsed, refractory, indolent or aggressive        non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma        (FL), chronic lymphocytic leukaemia (CLL), marginal zone        lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle        cell lymphoma (MCL), transformed lymphoma (TL), or peripheral        T-cell lymphoma (PTCL).

In still another distinct embodiment, the invention encompasses the useof a compound of formula (Ic):

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, wherein R² is as defined above,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, as a sole active agent,or of combinations of:a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof; andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of:

-   -   PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK        inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766        (RDEA-119));        or of pharmaceutical compositions containing such compounds or a        physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof,        or of pharmaceutical compositions containing such combinations,        for the preparation of a medicament for the treatment or        prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st        line, 2nd line, relapsed, refractory, indolent or aggressive        non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma        (FL), chronic lymphocytic leukaemia (CLL), marginal zone        lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle        cell lymphoma (MCL), transformed lymphoma (TL), or peripheral        T-cell lymphoma (PTCL).

In yet another distinct embodiment, the invention encompasses the use ofa compound of the formula (Id):

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, wherein Fe and Fe are as defined above,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, as a sole active agent,or of combinations of:a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof; andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of:

-   -   PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK        inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766        (RDEA-119));        or of pharmaceutical compositions containing such compounds or a        physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof,        or of pharmaceutical compositions containing such combinations,        for the preparation of a medicament for the treatment or        prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st        line, 2nd line, relapsed, refractory, indolent or aggressive        non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma        (FL), chronic lymphocytic leukaemia (CLL), marginal zone        lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle        cell lymphoma (MCL), transformed lymphoma (TL), or peripheral        T-cell lymphoma (PTCL).

In yet another distinct embodiment, the invention encompasses the use ofa compound of the formula (Ie):

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, wherein R² and Fe are as defined above,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, as a sole active agent,or of combinations of:a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof; andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of:

-   -   PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK        inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766        (RDEA-119));        or of pharmaceutical compositions containing such compounds or a        physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof,        or of pharmaceutical compositions containing such combinations,        for the preparation of a medicament for the treatment or        prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st        line, 2nd line, relapsed, refractory, indolent or aggressive        non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma        (FL), chronic lymphocytic leukaemia (CLL), marginal zone        lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle        cell lymphoma (MCL), transformed lymphoma (TL), or peripheral        T-cell lymphoma (PTCL).

In a preferred embodiment, the invention encompasses the use of acompound of formula (I)-(V), wherein Fe is pyridine, pyridazine,pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan or thiophene,optionally substituted with 1, 2 or 3 R⁶ groups; more preferrablywherein Fe is pyridine, pyridazine, pyrimidine, pyrazine, pyrole,oxazole or thiazole, optionally substituted with 1, 2 or 3 R⁶ groups,

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, as a sole active agent,or of combinations of:a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof; andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of:

-   -   PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK        inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766        (RDEA-119));        or of pharmaceutical compositions containing such compounds or a        physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof,        or of pharmaceutical compositions containing such combinations,        for the preparation of a medicament for the treatment or        prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st        line, 2nd line, relapsed, refractory, indolent or aggressive        non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma        (FL), chronic lymphocytic leukaemia (CLL), marginal zone        lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle        cell lymphoma (MCL), transformed lymphoma (TL), or peripheral        T-cell lymphoma (PTCL).

In still another preferred embodiment, the invention encompasses the useof a compound having the formula:

-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;-   N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-2,4-dimethyl-1,3-thiazole-5-carboxamide;-   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-thiazole-5-carboxamide;-   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]isonicotinamide;-   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-methyl-1,3-thiazole-5-carboxamide;-   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-propylpyrimidine-5-carboxamide;-   N-{8-[2-(4-ethylmorpholin-2-yl)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;-   N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide    1-oxide;-   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(2-pyrrolidin-1-ylethyl)nicotinamide;-   6-(cyclopentylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[8-(2-hydroxy-3-morpholin-4-ylpropoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-{7-methoxy-8-[3-(3-methylmorpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3′    dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-(8-{2-[4-(cyclobutylmethyl)morpholin-2-yl]ethoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-(7-methoxy-8-{2-[4-(2-methoxyethyl)morpholin-2-yl]ethoxy}-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-{8-[(4-ethylmorpholin-2-yl)methoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-(7-methoxy-8-{[4-(2-methoxyethyl)morpholin-2-yl]methoxy}-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-{7-methoxy-8-[(4-methylmorpholin-2-yl)methoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-4-carboxamide;-   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-4-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-methyl-1H-imidazole-4-carboxamide;-   rel-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;-   rel-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-6-methylnicotinamide;-   rel-6-acetamido-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-methyl-1H-imidazole-5-carboxamide;-   6-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-methylnicotinamide;-   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-methylpyrimidine-5-carboxamide;-   6-amino-5-bromo-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-oxazole-5-carboxamide;-   N-[7-methoxy-8-(morpholin-2-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   2-{[2-(dimethylamino)ethyl]amino}-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;-   2-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-1,3-thiazole-5-carboxamide;-   rel-2-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;-   rel-6-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   2-[(2-hydroxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-[(3-methoxypropyl)amino]pyrimidine-5-carboxamide;-   2-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-[(3-morpholin-4-ylpropyl)amino]pyrimidine-5-carboxamide;-   2-[(2-methoxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;-   2-{[2-(dimethylamino)ethyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;-   6-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-pyrrolidin-1-ylpyrimidine-5-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-morpholin-4-ylpyrimidine-5-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-piperazin-1-ylnicotinamide    hydrochloride;-   6-[(3S)-3-aminopyrrolidin-1-yl]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide    hydrochloride hydrate;-   6-[(3R)-3-aminopyrrolidin-1-yl]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide    hydrochloride;-   6-[(4-fluorobenzyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   6-[(2-furylmethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   6-[(2-methoxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(1H-pyrrol-1-yl)nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-morpholin-4-ylnicotinamide;-   N-{7-methoxy-8-[3-(methylamino)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   6-[(2,2-dimethylpropanoyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   6-[(cyclopropylcarbonyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(2,2,2-trifluoroethoxy)nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(trifluoromethyl)nicotinamide;-   6-(isobutyrylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3′    dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-{7-methoxy-8-[3-(4-methylpiperazin-1-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-{[(methylamino)carbonyl]amino}-1,3-thiazole-4-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-{[(methylamino)carbonyl]amino}nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(methylamino)-1,3-thiazole-4-carboxamide;-   N-[7-methoxy-8-(2-morpholin-4-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-2,4-dimethyl-1,3-thiazole-5-carboxamide;-   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-6-methylnicotinamide;-   6-[(isopropylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-pyrrolidin-1-ylnicotinamide;-   6-(dimethylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[7-methoxy-8-(3-piperidin-1-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[7-methoxy-8-(2-pyrrolidin-1-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[7-methoxy-8-(2-piperidin-1-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   6-{[(ethylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   6-fluoro-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-oxazole-4-carboxamide;-   2-(ethylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-thiazole-4-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrazine-2-carboxamide;-   N-[8-(2-aminoethoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   6-amino-N′[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]isonicotinamide;-   N-{8-[3-(diethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-{8-[2-(diisopropylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-{8-[2-(diethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(methylamino)pyrimidine-5-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(methylthio)pyrimidine-5-carboxamide;-   N-[8-(3-aminopropoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide    trifluoroacetate;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]thiophene-2-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2,4-dimethyl-1,3-thiazole-5-carboxamide;-   2-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-3-furamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]thiophene-3-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-methyl-1,3-thiazole-4-carboxamide;-   6-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   5-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-methylnicotinamide;-   6-(acetylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    or a physiologically acceptable salt, solvate, hydrate or    stereoisomer thereof, as a sole active agent,    or of combinations of:    a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a    physiologically acceptable salt, solvate, hydrate or stereoisomer    thereof; and    b) one or more further active agents, in particular an active agent    selected from an anti-angiogenesis, anti-hyper-proliferative,    antiinflammatory, analgesic, immunoregulatory, diuretic,    antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia,    anti-diabetic or antiviral agent, more particularly one or more    further active agents selected from the group consisting of:    -   PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK        inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766        (RDEA-119));        or of pharmaceutical compositions containing such compounds or a        physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof,        or of pharmaceutical compositions containing such combinations,        for the preparation of a medicament for the treatment or        prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st        line, 2nd line, relapsed, refractory, indolent or aggressive        non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma        (FL), chronic lymphocytic leukaemia (CLL), marginal zone        lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle        cell lymphoma (MCL), transformed lymphoma (TL), or peripheral        T-cell lymphoma (PTCL).

In a preferred embodiment, the invention encompasses the use of acompound having the formula:

-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-methylnicotinamide;-   5-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2,4-dimethyl-1,3-thiazole-5-carboxamide;-   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   6-{[(isopropylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-2,4-dimethyl-1,3-thiazole-5-carboxamide;-   N-[7-methoxy-8-(2-morpholin-4-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   rel-6-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   rel-2-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;-   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;-   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;    or a physiologically acceptable salt, solvate, hydrate or    stereoisomer thereof, as a sole active agent,    or of combinations of:    a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a    physiologically acceptable salt, solvate, hydrate or stereoisomer    thereof; and    b) one or more further active agents, in particular an active agent    selected from an anti-angiogenesis, anti-hyper-proliferative,    antiinflammatory, analgesic, immunoregulatory, diuretic,    antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia,    anti-diabetic or antiviral agent, more particularly one or more    further active agents selected from the group consisting of:    -   PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK        inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766        (RDEA-119));        or of pharmaceutical compositions containing such compounds or a        physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof,        or of pharmaceutical compositions containing such combinations,        for the preparation of a medicament for the treatment or        prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st        line, Ind line, relapsed, refractory, indolent or aggressive        non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma        (FL), chronic lymphocytic leukaemia (CLL), marginal zone        lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle        cell lymphoma (MCL), transformed lymphoma (TL), or peripheral        T-cell lymphoma (PTCL).

In a preferred embodiment, the invention encompasses the use of acompound having the formula:

2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof;as a sole active agent,or of pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof,for the preparation of a medicament for the treatment or prophylaxis ofnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL).

In a preferred embodiment, the invention encompasses the use of acompound having the formula:

2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamidedihydrochloride;as a sole active agent,or of pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof,for the preparation of a medicament for the treatment or prophylaxis ofnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL).

In a preferred embodiment, the invention encompasses the use ofcombinations of:

a)2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof; andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of:

-   -   PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK        inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766        (RDEA-119));        or of pharmaceutical compositions containing such a compound or        a physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof,        or of pharmaceutical compositions containing such combinations,        for the preparation of a medicament for the treatment or        prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st        line, 2nd line, relapsed, refractory, indolent or aggressive        non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma        (FL), chronic lymphocytic leukaemia (CLL), marginal zone        lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle        cell lymphoma (MCL), transformed lymphoma (TL), or peripheral        T-cell lymphoma (PTCL).

In a preferred embodiment, the invention encompasses the use ofcombinations of:

a)2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof; andb) a further active agent which is PI3Kδ-selective inhibitor GS-1101;or of pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof,or of pharmaceutical compositions containing such combinations,for the preparation of a medicament for the treatment or prophylaxis ofnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL).

In a preferred embodiment, the invention encompasses the use ofcombinations of:

a)2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof; andb) a further active agent which is BTK inhibitor ibrutinib;or of pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof,or of pharmaceutical compositions containing such combinations,for the preparation of a medicament for the treatment or prophylaxis ofnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL).

In a preferred embodiment, the invention encompasses the use ofcombinations of:

a)2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof; andb) a further active agent which is IKK inhibitor BAY Compound B;or of pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof,or of pharmaceutical compositions containing such combinations,for the preparation of a medicament for the treatment or prophylaxis ofnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL).

In a preferred embodiment, the invention encompasses the use ofcombinations of:

a)2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof; andb) a further active agent which is REFAMETINIB (BAY 86-9766 (RDEA-119));or of pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof,or of pharmaceutical compositions containing such combinations,for the preparation of a medicament for the treatment or prophylaxis ofnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL).

In a preferred embodiment, the invention encompasses the use ofcombinations of:

a)2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamidedihydrochloride; andb) a further active agent which is PI3Kδ-selective inhibitor GS-1101;or of pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof,or of pharmaceutical compositions containing such combinations,for the preparation of a medicament for the treatment or prophylaxis ofnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL).

In a preferred embodiment, the invention encompasses the use ofcombinations of:

a)2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamidedihydrochloride; andb) a further active agent which is BTK inhibitor ibrutinib;or of pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof,or of pharmaceutical compositions containing such combinations,for the preparation of a medicament for the treatment or prophylaxis ofnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL).

In a preferred embodiment, the invention encompasses the use ofcombinations of:

a)2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamidedihydrochloride; andb) a further active agent which is IKK inhibitor BAY Compound B;or of pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof,or of pharmaceutical compositions containing such combinations,for the preparation of a medicament for the treatment or prophylaxis ofnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL).

In a preferred embodiment, the invention encompasses the use ofcombinations of:

a)2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamidedihydrochloride; andb) a further active agent which is REFAMETINIB (BAY 86-9766 (RDEA-119));or of pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof,or of pharmaceutical compositions containing such combinations,for the preparation of a medicament for the treatment or prophylaxis ofnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL).

Where there is a discrepancy between the chemical name and the chemicalstructure depicted, the chemical structure depicted takes precedenceover the chemical name given.

Without being bound by theory or mechanism, the compounds of the presentinvention display surprising activity for the inhibition ofphosphatidylinositol-3-kinase and chemical and structural stability overthose compounds of the prior art. It is believed that this surprisingactivity is based on the chemical structure of the compounds, inparticular the basicity of the compounds as a result of R² being aminooptionally substituted with R⁵ and R^(5′). Further, the appropriatechoice of R³ and R² provide the necessary activity against theappropriate isoforms to allow for activity in vivo.

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer isnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL).

DEFINITIONS

The term ‘alkyl’ refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containingsolely of carbon and hydrogen atoms, containing no unsaturation, havingfrom one to eight carbon atoms, and which is attached to the rest of themolecule by a single bond, such as illustratively, methyl, ethyl,n-propyl 1-methylethyl (isopropyl), n-butyl, n-pentyl, and1,1-dimethylethyl (t-butyl).

The term “alkenyl” refers to an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be a straight or branched orbranched chain having about 2 to about 10 carbon atoms, e.g., ethenyl,1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl,1-butenyl, 2- and butenyl.

The term “alkynyl” refers to a straight or branched chain hydrocarbonylradicals having at least one carbon-carbon triple bond, and having inthe range of about 2 up to 12 carbon atoms (with radicals having in therange of about 2 up to 10 carbon atoms presently being preferred) e.g.,ethynyl.

The term “alkoxy” denotes an alkyl group as defined herein attached viaoxygen linkage to the rest of the molecule. Representative examples ofthose groups are methoxy and ethoxy.

The term “alkoxyakyl” denotes an alkoxy group as defined herein attachedvia oxygen linkage to an alkyl group which is then attached to the mainstructure at any carbon from alkyl group that results in the creation ofa stable structure the rest of the molecule. Representative examples ofthose groups are CH₂OCH₃, —CH₂OC₂H₅.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ringsystem of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and examples of multicyclic cycloalkyl groupsinclude perhydronapththyl, adamantyl and norbornyl groups bridged cyclicgroup or sprirobicyclic groups e.g sprio (4,4) non-2-yl.

The term “cycloalkylalkyl” refers to cyclic ring-containing radicalscontaining in the range of about 3 up to 8 carbon atoms directlyattached to alkyl group which is then also attached to the mainstructure at any carbon from the alkyl group that results in thecreation of a stable structure such as cyclopropylmethyl,cyclobuyylethyl, cyclopentylethyl.

The term “aryl” refers to aromatic radicals having in the range of 6 upto 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl,biphenyl.

The term “arylalkyl” refers to an aryl group as defined herein directlybonded to an alkyl group as defined herein which is then attached to themain structure at any carbon from alkyl group that results in thecreation of a stable structure the rest of the molecule. e.g., —CH₂C₆H₅,—C₂H₅C₆H₅.

The term “heterocyclic ring” refers to a stable 3- to 15 membered ringradical which consists of carbon atoms and from one to five heteroatomsselected from the group consisting of nitrogen, phosphorus, oxygen andsulfur. For purposes of this invention, the heterocyclic ring radicalmay be a monocyclic, bicyclic or tricyclic ring system, which mayinclude fused, bridged or spiro ring systems, and the nitrogen,phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ringradical may be optionally oxidized to various oxidation states. Inaddition, the nitrogen atom may be optionally quaternized;

and the ring radical may be partially or fully saturated (i.e.,heteroaromatic or heteroaryl aromatic). Examples of such heterocyclicring radicals include, but are not limited to, azetidinyl, acridinyl,benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl cinnolinyldioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazil, pyridyl, pteridinyl, purinyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl,imidazolyl tetrahydroisouinolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl,azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinylpyridazinyl, oxazolyl oxazolinyl oxasolidinyl, triazolyl, indanyl,isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl,thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl,isoindolyl, indolinyl, isoindolinyl, octahydroindolyl,octahydroisoindolyl quinolyl, isoquinolyl, decahydroisoquinolyl,benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl,benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl,benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide thiamorpholinylsulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, isochromanyl.

The term “heteroaryl” refers to heterocyclic ring radical as definedherein which are aromatic. The heteroaryl ring radical may be attachedto the main structure at any heteroatom or carbon atom that results inthe creation of a stable structure.

The heterocyclic ring radical may be attached to the main structure atany heteroatom or carbon atom that results in the creation of a stablestructure.

The term “heteroarylalkyl” refers to heteroaryl ring radical as definedherein directly bonded to alkyl group. The heteroarylalkyl radical maybe attached to the main structure at any carbon atom from alkyl groupthat results in the creation of a stable structure.

The term “heterocyclyl” refers to a heterocylic ring radical as definedherein. The heterocylyl ring radical may be attached to the mainstructure at any heteroatom or carbon atom that results in the creationof a stable structure.

The term “heterocyclylalkyl” refers to a heterocylic ring radical asdefined herein directly bonded to alkyl group. The heterocyclylalkylradical may be attached to the main structure at carbon atom in thealkyl group that results in the creation of a stable structure.

The term “carbonyl” refers to an oxygen atom bound to a carbon atom ofthe molecule by a double bond.

The term “halogen” refers to radicals of fluorine, chlorine, bromine andiodine.

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

The compounds of this invention may contain one or more asymmetriccenters, depending upon the location and nature of the varioussubstituents desired. Asymmetric carbon atoms may be present in the (R)or (S) configuration, resulting in racemic mixtures in the case of asingle asymmetric center, and diastereomeric mixtures in the case ofmultiple asymmetric centers. In certain instances, asymmetry may also bepresent due to restricted rotation about a given bond, for example, thecentral bond adjoining two substituted aromatic rings of the specifiedcompounds. Substituents on a ring may also be present in either cis ortrans form. It is intended that all such configurations (includingenantiomers and diastereomers), are included within the scope of thepresent invention. Preferred compounds are those, which produce the moredesirable biological activity. Separated, pure or partially purifiedisomers and stereoisomers or racemic or diastereomeric mixtures of thecompounds of this invention are also included within the scope of thepresent invention. The purification and the separation of such materialscan be accomplished by standard techniques known in the art.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as pharmaceutically acceptable salts,co-precipitates, metabolites, hydrates, solvates and prodrugs of all thecompounds of examples. The term “pharmaceutically acceptable salt”refers to a relatively non-toxic, inorganic or organic acid additionsalt of a compound of the present invention. For example, see S. M.Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.Pharmaceutically acceptable salts include those obtained by reacting themain compound, functioning as a base, with an inorganic or organic acidto form a salt, for example, salts of hydrochloric acid, sulfuric acid,phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalicacid, maleic acid, succinic acid and citric acid. Pharmaceuticallyacceptable salts also include those in which the main compound functionsas an acid and is reacted with an appropriate base to form, e.g.,sodium, potassium, calcium, magnesium, ammonium, and chorine salts.

Those skilled in the art will further recognize that acid addition saltsof the claimed compounds may be prepared by reaction of the compoundswith the appropriate inorganic or organic acid via any of a number ofknown methods. Alternatively, alkali and alkaline earth metal salts ofacidic compounds of the invention are prepared by reacting the compoundsof the invention with the appropriate base via a variety of knownmethods.

Representative salts of the compounds of this invention include theconventional non-toxic salts and the quaternary ammonium salts which areformed, for example, from inorganic or organic acids or bases by meanswell known in the art. For example, such acid addition salts includeacetate, adipate, alginate, ascorbate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide,iodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate,mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate,picrate, pivalate, propionate, succinate, sulfonate, sulfate, tartrate,thiocyanate, tosylate, and undecanoate.

Base salts include alkali metal salts such as potassium and sodiumsalts, alkaline earth metal salts such as calcium and magnesium salts,and ammonium salts with organic bases such as dicyclohexylamine andN-methyl-D-glucamine. Additionally, basic nitrogen containing groups maybe quaternized with such agents as lower alkyl halides such as methyl,ethyl, propyl, or butyl chlorides, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl sulfate, or diamyl sulfates,long chain halides such as decyl, lauryl, myristyl and strearylchlorides, bromides and iodides, aralkyl halides like benzyl andphenethyl bromides and others.

A solvate for the purpose of this invention is a complex of a solventand a compound of the invention in the solid state. Exemplary solvateswould include, but are not limited to, complexes of a compound of theinvention with ethanol or methanol. Hydrates are a specific form ofsolvate wherein the solvent is water.

The synthesis of the compounds listed above is described inInternational Patent Application No. PCT/EP2003/010377, published as WO2004/029055 A1, and in International Patent Application No.PCT/US2007/024985, published as WO 2008/070150, both of which are herebyincorporated herein in their entirety by reference.

In accordance with another embodiment, the present invention relates toa 2,3-dihydroimidazo[1,2-c]quinazoline compound as defined herein, inparticular2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, as a sole agent, for the treatment of non-Hodgkin's lymphoma(NHL), particularly 1st line, 2nd line, relapsed, refractory, indolentor aggressive non-Hodgkin's lymphoma (NHL), in particular follicularlymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zonelymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle celllymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma(PTCL).

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer isnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL).

Combination Therapies

As mentioned supra, the present invention relates to combinations of:

a) a 2,3-dihydroimidazo[1,2-c]quinazoline compound as defined supra, ora physiologically acceptable salt, solvate, hydrate or stereoisomerthereof; or pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof;andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of:

-   -   PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK        inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766        (RDEA-119)).

In a preferred embodiment, the invention encompasses combinations of:

a)2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof; or pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof;andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of:

-   -   PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK        inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766        (RDEA-119)).

In a preferred embodiment, the invention encompasses combinations of:

a)2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof; or pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof;andb) one or more further active agents selected from the group consistingof: PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKKinhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766 (RDEA-119)).

In a preferred embodiment, the invention encompasses combinations of:

a)2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof; or pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof;andb) a further active agent which is PI3Kδ-selective inhibitor GS-1101.

In a preferred embodiment, the invention encompasses combinations of:

a)2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof; or pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof;andb) a further active agent which is BTK inhibitor ibrutinib.

In a preferred embodiment, the invention encompasses combinations of:

a)2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof; or pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof; andb) a further active agent which is IKK inhibitor BAY Compound B.

In a preferred embodiment, the invention encompasses combinations of:

a)2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof; or pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof;andb) a further active agent which is REFAMETINIB (BAY 86-9766 (RDEA-119)).

In a preferred embodiment, the invention encompasses the use ofcombinations of:

a)2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof; or pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof;andb) a further active agent which is PI3Kδ-selective inhibitor GS-1101.

In a preferred embodiment, the invention encompasses the use ofcombinations of:

a)2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof; or pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof;andb) a further active agent which is BTK inhibitor ibrutinib.

In a preferred embodiment, the invention encompasses the use ofcombinations of:

a)2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof; or pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof;andb) a further active agent which is IKK inhibitor BAY Compound B.

In a preferred embodiment, the invention encompasses the use ofcombinations of:

a)2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof; or pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof;andb) a further active agent which is REFAMETINIB (BAY 86-9766 (RDEA-119)).

The compounds of this invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutical agents (or “further active agents”) where the combinationcauses no unacceptable adverse effects. For example, the compounds ofthis invention can be combined with known anti-angiogenesis,anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory,diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia,anti-diabetic or antiviral agents, and the like, as well as withadmixtures and combinations thereof.

The additional pharmaceutical agent or agents (or “further activeagent”) can be, but are not limited to 131I-chTNT, abarelix,abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin,altretamine, aminoglutethimide, amrubicin, amsacrine, anastrozole,arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY1000394, refametinib (BAY 86-9766 (RDEA 119)), belotecan, bendamustine,bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin,bortezomib, buserelin, busulfan, cabazitaxel, calcium folinate, calciumlevofolinate, capecitabine, carboplatin, carmofur, carmustine,catumaxomab, celecoxib, celmoleukin, cetuximab, chlorambucil,chlormadinone, chlormethine, cisplatin, cladribine, clodronic acid,clofarabine, crisantaspase, cyclophosphamide, cyproterone, cytarabine,dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin,decitabine, degarelix, denileukin diftitox, denosumab, deslorelin,dibrospidium chloride, docetaxel, doxifluridine, doxorubicin,doxorubicin+estrone, eculizumab, edrecolomab, elliptinium acetate,eltrombopag, endostatin, enocitabine, epirubicin, epitiostanol, epoetinalfa, epoetin beta, eptaplatin, eribulin, erlotinib, estradiol,estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim,fludarabine, fluorouracil, flutamide, formestane, fotemustine,fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine,gemtuzumab, glutoxim, goserelin, histamine dihydrochloride, histrelin,hydroxycarbamide, I-125 seeds, ibandronic acid, ibritumomab tiuxetan,idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferonalfa, interferon beta, interferon gamma, ipilimumab, irinotecan,ixabepilone, lanreotide, lapatinib, lenalidomide, lenograstim, lentinan,letrozole, leuprorelin, levamisole, lisuride, lobaplatin, lomustine,lonidamine, masoprocol, medroxyprogesterone, megestrol, melphalan,mepitiostane, mercaptopurine, methotrexate, methoxsalen, Methylaminolevulinate, methyltestosterone, mifamurtide, miltefosine,miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane,mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide,nimotuzumab, nimustine, nitracrine, obinutuzumab, ofatumumab,omeprazole, oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel,palifermin, palladium-103 seed, pamidronic acid, panitumumab, pazopanib,pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta),pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine,pentostatin, peplomycin, perfosfamide, picibanil, pirarubicin,plerixafor, plicamycin, poliglusam, polyestradiol phosphate,polysaccharide-K, porfimer sodium, pralatrexate, prednimustine,procarbazine, quinagolide, raloxifene, raltitrexed, ranimustine,razoxane, regorafenib, risedronic acid, rituximab, romidepsin,romiplostim, sargramostim, sipuleucel-T, sizofiran, sobuzoxane, sodiumglycididazole, sorafenib, streptozocin, sunitinib, talaporfin,tamibarotene, tamoxifen, tasonermin, teceleukin, tegafur,tegafur+gimeracil+oteracil, temoporfin, temozolomide, temsirolimus,teniposide, testosterone, tetrofosmin, thalidomide, thiotepa,thymalfasin, tioguanine, tocilizumab, topotecan, toremifene,tositumomab, trabectedin, trastuzumab, treosulfan, tretinoin,trilostane, triptorelin, trofosfamide, tryptophan, ubenimex, valrubicin,vandetanib, vapreotide, vemurafenib, vinblastine, vincristine,vindesine, vinflunine, vinorelbine, vorinostat, vorozole, yttrium-90glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid,zorubicin, or a combination thereof.

The additional pharmaceutical agent or agents (or “further activeagent”) can be, but are not limited to aldesleukin, alendronic acid,alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine,aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole,anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine,azathioprine, BCG or tice BCG, bestatin, betamethasone acetate,betamethasone sodium phosphate, bexarotene, bleomycin sulfate,broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine,carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil,cisplatin, cladribine, cladribine, clodronic acid, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, DaunoXome, decadron, decadronphosphate, delestrogen, denileukin diftitox, depo-medrol, deslorelin,dexomethasone, dexrazoxane, diethylstilbestrol, diflucan, docetaxel,doxifluridine, doxorubicin, dronabinol, DW-166HC, eligard, elitek,ellence, emend, epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol,estrace, estradiol, estramustine phosphate sodium, ethinyl estradiol,ethyol, etidronic acid, etopophos, etoposide, fadrozole, farston,filgrastim, finasteride, fligrastim, floxuridine, fluconazole,fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU),fluoxymesterone, flutamide, formestane, fosteabine, fotemustine,fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel,goserelin, granisetron HCl, herceptin, histrelin, hycamtin,hydrocortone, eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomabtiuxetan, idarubicin, ifosfamide, interferon alpha, interferon-alpha 2,interferon alfa-2A, interferon alfa-2B, interferon alfa-n1, interferonalfa-n3, interferon beta, interferon gamma-la, interleukin-2, intron A,iressa, irinotecan, kytril, lapatinib, lentinan sulphate, letrozole,leucovorin, leuprolide, leuprolide acetate, lenalidomide, levamisole,levofolinic acid calcium salt, levothroid, levoxyl, lomustine,lonidamine, marinol, mechlorethamine, mecobalamin, medroxyprogesteroneacetate, megestrol acetate, melphalan, menest, 6-mercaptopurine, Mesna,methotrexate, metvix, miltefosine, minocycline, mitomycin C, mitotane,mitoxantrone, Modrenal, Myocet, nedaplatin, neulasta, neumega, neupogen,nilutamide, nolvadex, NSC-631570, OCT-43, octreotide, ondansetron HCl,orapred, oxaliplatin, paclitaxel, pediapred, pegaspargase, Pegasys,pentostatin, picibanil, pilocarpine HCl, pirarubicin, plicamycin,porfimer sodium, prednimustine, prednisolone, prednisone, premarin,procarbazine, procrit, refametinib (BAY 86-9766 (RDEA 119)),raltitrexed, rebif, rhenium-186 etidronate, rituximab, roferon-A,romurtide, salagen, sandostatin, sargramostim, semustine, sizofiran,sobuzoxane, solu-medrol, sparfosic acid, stem-cell therapy,streptozocin, strontium-89 chloride, sunitinib, synthroid, tamoxifen,tamsulosin, tasonermin, tastolactone, taxotere, teceleukin,temozolomide, teniposide, testosterone propionate, testred, thioguanine,thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene,tositumomab, trastuzumab, treosulfan, tretinoin, trexall,trimethylmelamine, trimetrexate, triptorelin acetate, triptorelinpamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine,vincristine, vindesine, vinorelbine, virulizin, zinecard, zinostatinstimalamer, zofran, ABI-007, acolbifene, actimmune, affinitak,aminopterin, arzoxifene, asoprisnil, atamestane, atrasentan, BAY 43-9006(sorafenib), avastin, CCI-779, CDC-501, celebrex, cetuximab, crisnatol,cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM,dutasteride, edotecarin, eflornithine, exatecan, fenretinide, histaminedihydrochloride, histrelin hydrogel implant, holmium-166 DOTMP,ibandronic acid, interferon gamma, intron-PEG, ixabepilone, keyholelimpet hemocyanin, L-651582, lanreotide, lasofoxifene, libra,lonafarnib, miproxifene, minodronate, MS-209, liposomal MTP-PE, MX-6,nafarelin, nemorubicin, neovastat, nolatrexed, oblimersen, onco-TCS,osidem, paclitaxel polyglutamate, pamidronate disodium, PN-401, QS-21,quazepam, R-1549, raloxifene, ranpirnase, 13-cis-retinoic acid,satraplatin, seocalcitol, T-138067, tarceva, taxoprexin, thalidomide,thymosin alpha 1, tiazofurine, tipifarnib, tirapazamine, TLK-286,toremifene, TransMID-107R, valspodar, vapreotide, vatalanib,verteporfin, vinflunine, Z-100, zoledronic acid or combinations thereof.

In accordance with an embodiment, the additional pharmaceutical agent oragents (or “further active agent”) is selected from the group consistingof: 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin,alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin,amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase,azacitidine, basiliximab, BAY 1000394, refametinib (BAY 86-9766 (RDEA119)), belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide,bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel,calcium folinate, calcium levofolinate, capecitabine, carboplatin,carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cetuximab,chlorambucil, chlormadinone, chlormethine, cisplatin, cladribine,clodronic acid, clofarabine, crisantaspase, cyclophosphamide,cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa,dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox,denosumab, deslorelin, dibrospidium chloride, docetaxel, doxifluridine,doxorubicin, doxorubicin+estrone, eculizumab, edrecolomab, elliptiniumacetate, eltrombopag, endostatin, enocitabine, epirubicin, epitiostanol,epoetin alfa, epoetin beta, eptaplatin, eribulin, erlotinib, estradiol,estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim,fludarabine, fluorouracil, flutamide, formestane, fotemustine,fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine,gemtuzumab, glutoxim, goserelin, histamine dihydrochloride, histrelin,hydroxycarbamide, I-125 seeds, ibandronic acid, ibritumomab tiuxetan,idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferonalfa, interferon beta, interferon gamma, ipilimumab, irinotecan,ixabepilone, lanreotide, lapatinib, lenalidomide, lenograstim, lentinan,letrozole, leuprorelin, levamisole, lisuride, lobaplatin, lomustine,lonidamine, masoprocol, medroxyprogesterone, megestrol, melphalan,mepitiostane, mercaptopurine, methotrexate, methoxsalen, Methylaminolevulinate, methyltestosterone, mifamurtide, miltefosine,miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane,mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide,nimotuzumab, nimustine, nitracrine, ofatumumab, omeprazole, oprelvekin,oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium-103seed, pamidronic acid, panitumumab, pazopanib, pegaspargase, PEG-epoetinbeta (methoxy PEG-epoetin beta), pegfilgrastim, peginterferon alfa-2b,pemetrexed, pentazocine, pentostatin, peplomycin, perfosfamide,picibanil, pirarubicin, plerixafor, plicamycin, poliglusam,polyestradiol phosphate, polysaccharide-K, porfimer sodium,pralatrexate, prednimustine, procarbazine, quinagolide, raloxifene,raltitrexed, ranimustine, razoxane, regorafenib, risedronic acid,rituximab, romidepsin, romiplostim, sargramostim, sipuleucel-T,sizofiran, sobuzoxane, sodium glycididazole, sorafenib, streptozocin,sunitinib, talaporfin, tamibarotene, tamoxifen, tasonermin, teceleukin,tegafur, tegafur+gimeracil+oteracil, temoporfin, temozolomide,temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide,thiotepa, thymalfasin, tioguanine, tocilizumab, topotecan, toremifene,tositumomab, trabectedin, trastuzumab, treosulfan, tretinoin,trilostane, triptorelin, trofosfamide, tryptophan, ubenimex, valrubicin,vandetanib, vapreotide, vemurafenib, vinblastine, vincristine,vindesine, vinflunine, vinorelbine, vorinostat, vorozole, yttrium-90glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid,zorubicin.

The additional pharmaceutical agent can also be gemcitabine, paclitaxel,cisplatin, carboplatin, sodium butyrate, 5-FU, doxirubicin, tamoxifen,etoposide, trastumazab, gefitinib, intron A, rapamycin, 17-AAG, U0126,insulin, an insulin derivative, a PPAR ligand, a sulfonylurea drug, anα-glucosidase inhibitor, a biguanide, a PTP-1B inhibitor, a DPP-IVinhibitor, a 11-beta-HSD inhibitor, GLP-1, a GLP-1 derivative, GIP, aGIP derivative, PACAP, a PACAP derivative, secretin or a secretinderivative.

Optional anti-hyper-proliferative agents which can be added to thecomposition include but are not limited to compounds listed on thecancer chemotherapy drug regimens in the 11^(th) Edition of the MerckIndex, (1996), which is hereby incorporated by reference, such asasparaginase, bleomycin, carboplatin, carmustine, chlorambucil,cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine,dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin,etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide,irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine,mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone,prednisone, procarbazine, raloxifen, streptozocin, tamoxifen,thioguanine, topotecan, vinblastine, vincristine, and vindesine.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to thosecompounds acknowledged to be used in the treatment of neoplasticdiseases in Goodman and Gilman's The Pharmacological Basis ofTherapeutics (Ninth Edition), editor Molinoff et al., publ. byMcGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated byreference, such as aminoglutethimide, L-asparaginase, azathioprine,5-azacytidine cladribine, busulfan, diethylstilbestrol,2′,2′-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine,ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridinemonophosphate, fludarabine phosphate, fluoxymesterone, flutamide,hydroxyprogesterone caproate, idarubicin, interferon,medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane,paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA),plicamycin, semustine, teniposide, testosterone propionate, thiotepa,trimethylmelamine, uridine, and vinorelbine.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to otheranti-cancer agents such as epothilone and its derivatives, irinotecan,raloxifen and topotecan.

Generally, the use of cytotoxic and/or cytostatic agents in combinationwith a compound or composition of the present invention will serve to:

(1) yield better efficacy in reducing the growth of a tumor or eveneliminate the tumor as compared to administration of either agent alone,(2) provide for the administration of lesser amounts of the administeredchemotherapeutic agents,(3) provide for a chemotherapeutic treatment that is better tolerated inthe patient with fewer deleterious pharmacological complications thanobserved with single agent chemotherapies and certain other combinedtherapies,(4) provide for treating a broader spectrum of different cancer types inmammals, especially humans,(5) provide for a higher response rate among treated patients,(6) provide for a longer survival time among treated patients comparedto standard chemotherapy treatments,(7) provide a longer time for tumor progression, and/or(8) yield efficacy and tolerability results at least as good as those ofthe agents used alone, compared to known instances where other canceragent combinations produce antagonistic effects.

In accordance with an embodiment, the invention relates to combinationswherein said 2,3-dihydroimidazo[1,2-c]quinazoline compound is2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide.

In accordance with an embodiment, the invention relates to combinationswherein said 2,3-dihydroimidazo[1,2-c]quinazoline compound is2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamidedihydrochloride.

In accordance with an embodiment, the invention relates to combinationswherein said 2,3-dihydroimidazo[1,2-c]quinazoline compound is2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamideand said further active agent is PI3Kδ-selective inhibitor GS-1101.

In accordance with an embodiment, the invention relates to combinationswherein said 2,3-dihydroimidazo[1,2-c]quinazoline compound is2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamideand said further active agent is BTK inhibitor ibrutinib.

In accordance with an embodiment, the invention relates to combinationswherein said 2,3-dihydroimidazo[1,2-c]quinazoline compound is2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamideand said further active agent is REFAMETINIB (BAY 86-9766 (RDEA-119)).

In accordance with an embodiment, the invention relates to combinationswherein said 2,3-dihydroimidazo[1,2-c]quinazoline compound is2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamidedihydrochloride and said further active agent is PI3Kδ-selectiveinhibitor GS-1101.

In accordance with an embodiment, the invention relates to combinationswherein said 2,3-dihydroimidazo[1,2-c]quinazoline compound is2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamidedihydrochloride and said further active agent is BTK inhibitoribrutinib.

In accordance with an embodiment, the invention relates to combinationswherein said 2,3-dihydroimidazo[1,2-c]quinazoline compound is2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamidedihydrochloride and said further active agent is IKK inhibitor BAYCompound B.

In accordance with an embodiment, the invention relates to combinationswherein said 2,3-dihydroimidazo[1,2-c]quinazoline compound is2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamidedihydrochloride and said further active agent is REFAMETINIB (BAY86-9766 (RDEA-119)).

Pharmaceutical Compositions of the Compounds of the Invention

As mentioned supra, the present invention relates to pharmaceuticalcompositions:

-   -   comprising a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a        physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof, as a sole active agent, for the treatment        of non-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd        line, relapsed, refractory, indolent or aggressive non-Hodgkin's        lymphoma (NHL), in particular follicular lymphoma (FL), chronic        lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL),        diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma        (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma        (PTCL), and        -   comprising a pharmaceutical composition which comprises a            combination of:        -   a) a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a            physiologically acceptable salt, solvate, hydrate or            stereoisomer thereof; and        -   b) one or more further active agents, in particular an            active agent selected from an anti-angiogenesis,            anti-hyper-proliferative, antiinflammatory, analgesic,            immunoregulatory, diuretic, antiarrhytmic,            anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic            or antiviral agent, more particularly one or more further            active agents selected from the group consisting of:        -   PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib,            IKK inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766            (RDEA-119)).

In accordance with another embodiment, the present invention relates topharmaceutical compositions which comprise a2,3-dihydroimidazo[1,2-c]quinazoline compound as defined herein, inparticular2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, as a sole agent, for the treatment of non-Hodgkin's lymphoma(NHL), particularly 1st line, 2nd line, relapsed, refractory, indolentor aggressive non-Hodgkin's lymphoma (NHL), in particular follicularlymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zonelymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle celllymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma(PTCL).

In accordance with another embodiment, the present invention relates topharmaceutical compositions which comprise2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamidedihydrochloride, as a sole agent, for the treatment of non-Hodgkin'slymphoma (NHL), particularly 1st line, 2nd line, relapsed, refractory,indolent or aggressive non-Hodgkin's lymphoma (NHL), in particularfollicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginalzone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle celllymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma(PTCL).

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer isnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL).

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer isnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL).

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer is follicularlymphoma (FL).

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer is chroniclymphocytic leukaemia (CLL).

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer is marginalzone lymphoma (MZL).

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer is diffuselarge B-cell lymphoma (DLBCL).

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer is mantlecell lymphoma (MCL).

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer istransformed lymphoma (TL).

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer is peripheralT-cell lymphoma (PTCL).

Said pharmaceutical compositions contain one or more compounds. Thesecompositions can be utilized to achieve the desired pharmacologicaleffect by administration to a patient in need thereof. A patient, forthe purpose of this invention, is a mammal, including a human, in needof treatment for the particular condition or disease. Therefore, thepresent invention includes pharmaceutical compositions that arecomprised of a pharmaceutically acceptable carrier and apharmaceutically effective amount of a compound, or salt thereof, of thepresent invention. A pharmaceutically acceptable carrier is preferably acarrier that is relatively non-toxic and innocuous to a patient atconcentrations consistent with effective activity of the active agent sothat any side effects ascribable to the carrier do not vitiate thebeneficial effects of the active agent. A pharmaceutically effectiveamount of compound is preferably that amount which produces a result orexerts an influence on the particular condition being treated. Thecompounds of the present invention can be administered withpharmaceutically-acceptable carriers well known in the art using anyeffective conventional dosage unit forms, including immediate, slow andtimed release preparations, orally, parenterally, topically, nasally,ophthalmically, optically, sublingually, rectally, vaginally, and thelike.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, lozenges,melts, powders, solutions, suspensions, or emulsions, and may beprepared according to methods known to the art for the manufacture ofpharmaceutical compositions. The solid unit dosage forms can be acapsule that can be of the ordinary hard- or soft-shelled gelatin typecontaining, for example, surfactants, lubricants, and inert fillers suchas lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose and cornstarchin combination with binders such as acacia, corn starch or gelatin,disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum, gum tragacanth, acacia, lubricants intendedto improve the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample talc, stearic acid, or magnesium, calcium or zinc stearate,dyes, coloring agents, and flavoring agents such as peppermint, oil ofwintergreen, or cherry flavoring, intended to enhance the aestheticqualities of the tablets and make them more acceptable to the patient.Suitable excipients for use in oral liquid dosage forms includedicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance tablets, pills or capsules may be coated withshellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active agent in admixture with adispersing or wetting agent, a suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above.

Additional excipients, for example those sweetening, flavoring andcoloring agents described above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived form fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active agent in avegetable oil such as, for example, arachis oil, olive oil, sesame oilor coconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more coloring agents; one or more flavoringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavoring and coloring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intraocularly, intrasynovially,intramuscularly, or interperitoneally, as injectable dosages of thecompound in preferably a physiologically acceptable diluent with apharmaceutical carrier which can be a sterile liquid or mixture ofliquids such as water, saline, aqueous dextrose and related sugarsolutions, an alcohol such as ethanol, isopropanol, or hexadecylalcohol, glycols such as propylene glycol or polyethylene glycol,glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, etherssuch as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acidester or, a fatty acid glyceride, or an acetylated fatty acid glyceride,with or without the addition of a pharmaceutically acceptable surfactantsuch as a soap or a detergent, suspending agent such as pectin,carbomers, methycellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agent and other pharmaceuticaladjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid. Suitable fatty acid esters are, for example, ethyl oleate andisopropyl myristate. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts and suitable detergents includecationic detergents, for example dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,for example, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active agent in solution.Preservatives and buffers may also be used advantageously. In order tominimize or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) preferably of from about 12 to about17. The quantity of surfactant in such formulation preferably rangesfrom about 5% to about 15% by weight. The surfactant can be a singlecomponent having the above HLB or can be a mixture of two or morecomponents having the desired HLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcell u lose,methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are, for example, cocoa butter and polyethyleneglycol.

Another formulation employed in the methods of the present inventionemploys transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds of the present invention in controlled amounts. Theconstruction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No.5,023,252, issued Jun. 11, 1991, incorporated herein by reference). Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations that areknown in the art.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. Direct techniques for,for example, administering a drug directly to the brain usually involveplacement of a drug delivery catheter into the patient's ventricularsystem to bypass the blood-brain barrier. One such implantable deliverysystem, used for the transport of agents to specific anatomical regionsof the body, is described in U.S. Pat. No. 5,011,472, issued Apr. 30,1991.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Conventionalprocedures for preparing such compositions in appropriate dosage formscan be utilized. Such ingredients and procedures include those describedin the following references, each of which is incorporated herein byreference: Powell, M. F. et al, “Compendium of Excipients for ParenteralFormulations” PDA Journal of Pharmaceutical Science & Technology 1998,52(5), 238-311; Strickley, R. G “Parenteral Formulations of SmallMolecule Therapeutics Marketed in the United States (1999)-Part-1” PDAJournal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; andNema, S. et al, “Excipients and Their Use in Injectable Products” PDAJournal of Pharmaceutical Science & Technology 1997, 51(4), 166-171.

Commonly used pharmaceutical ingredients that can be used as appropriateto formulate the composition for its intended route of administrationinclude:

acidifying agents (examples include but are not limited to acetic acid,citric acid, fumaric acid, hydrochloric acid, nitric acid);alkalinizing agents (examples include but are not limited to ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide,triethanolamine, trolamine);adsorbents (examples include but are not limited to powdered celluloseand activated charcoal);aerosol propellants (examples include but are not limited to carbondioxide, CCl₂F₂, F₂ClC—CClF2 and CClF₃)air displacement agents (examples include but are not limited tonitrogen and argon); antifungal preservatives (examples include but arenot limited to benzoic acid, butylparaben, ethylparaben, methylparaben,propylparaben, sodium benzoate);antimicrobial preservatives (examples include but are not limited tobenzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,phenylmercuric nitrate and thimerosal);antioxidants (examples include but are not limited to ascorbic acid,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate,sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite);binding materials (examples include but are not limited to blockpolymers, natural and synthetic rubber, polyacrylates, polyurethanes,silicones, polysiloxanes and styrene-butadiene copolymers);buffering agents (examples include but are not limited to potassiummetaphosphate, dipotassium phosphate, sodium acetate, sodium citrateanhydrous and sodium citrate dihydrate)carrying agents (examples include but are not limited to acacia syrup,aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orangesyrup, syrup, corn oil, mineral oil, peanut oil, sesame oil,bacteriostatic sodium chloride injection and bacteriostatic water forinjection)chelating agents (examples include but are not limited to edetatedisodium and edetic acid)colorants (examples include but are not limited to FD&C Red No. 3, FD&CRed No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&COrange No. 5, D&C Red No. 8, caramel and ferric oxide red);clarifying agents (examples include but are not limited to bentonite);emulsifying agents (examples include but are not limited to acacia,cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitanmonooleate, polyoxyethylene 50 monostearate);encapsulating agents (examples include but are not limited to gelatinand cellulose acetate phthalate)flavorants (examples include but are not limited to anise oil, cinnamonoil, cocoa, menthol, orange oil, peppermint oil and vanillin);humectants (examples include but are not limited to glycerol, propyleneglycol and sorbitol);levigating agents (examples include but are not limited to mineral oiland glycerin);oils (examples include but are not limited to arachis oil, mineral oil,olive oil, peanut oil, sesame oil and vegetable oil);ointment bases (examples include but are not limited to lanolin,hydrophilic ointment, polyethylene glycol ointment, petrolatum,hydrophilic petrolatum, white ointment, yellow ointment, and rose waterointment);penetration enhancers (transdermal delivery) (examples include but arenot limited to monohydroxy or polyhydroxy alcohols, mono- or polyvalentalcohols, saturated or unsaturated fatty alcohols, saturated orunsaturated fatty esters, saturated or unsaturated dicarboxylic acids,essential oils, phosphatidyl derivatives, cephalin, terpenes, amides,ethers, ketones and ureas)plasticizers (examples include but are not limited to diethyl phthalateand glycerol);solvents (examples include but are not limited to ethanol, corn oil,cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanutoil, purified water, water for injection, sterile water for injectionand sterile water for irrigation); stiffening agents (examples includebut are not limited to cetyl alcohol, cetyl esters wax, microcrystallinewax, paraffin, stearyl alcohol, white wax and yellow wax);suppository bases (examples include but are not limited to cocoa butterand polyethylene glycols (mixtures));surfactants (examples include but are not limited to benzalkoniumchloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium laurylsulfate and sorbitan mono-palmitate);suspending agents (examples include but are not limited to agar,bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,kaolin, methylcellulose, tragacanth and veegum);sweetening agents (examples include but are not limited to aspartame,dextrose, glycerol, mannitol, propylene glycol, saccharin sodium,sorbitol and sucrose);tablet anti-adherents (examples include but are not limited to magnesiumstearate and talc);tablet binders (examples include but are not limited to acacia, alginicacid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose,gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);tablet and capsule diluents (examples include but are not limited todibasic calcium phosphate, kaolin, lactose, mannitol, microcrystallinecellulose, powdered cellulose, precipitated calcium carbonate, sodiumcarbonate, sodium phosphate, sorbitol and starch);tablet coating agents (examples include but are not limited to liquidglucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetatephthalate and shellac); tablet direct compression excipients (examplesinclude but are not limited to dibasic calcium phosphate);tablet disintegrants (examples include but are not limited to alginicacid, carboxymethylcellulose calcium, microcrystalline cellulose,polacrillin potassium, crosslinked polyvinylpyrrolidone, sodiumalginate, sodium starch glycollate and starch);tablet glidants (examples include but are not limited to colloidalsilica, corn starch and talc);tablet lubricants (examples include but are not limited to calciumstearate, magnesium stearate, mineral oil, stearic acid and zincstearate);tablet/capsule opaquants (examples include but are not limited totitanium dioxide);tablet polishing agents (examples include but are not limited to carnubawax and white wax);thickening agents (examples include but are not limited to beeswax,cetyl alcohol and paraffin);tonicity agents (examples include but are not limited to dextrose andsodium chloride); viscosity increasing agents (examples include but arenot limited to alginic acid, bentonite, carbomers,carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone,sodium alginate and tragacanth); andwetting agents (examples include but are not limited toheptadecaethylene oxycetanol, lecithins, sorbitol monooleate,polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions according to the present invention can beillustrated as follows:

Sterile IV Solution: A 5 mg/mL solution of the desired compound of thisinvention can be made using sterile, injectable water, and the pH isadjusted if necessary. The solution is diluted for administration to I-2mg/mL with sterile 5% dextrose and is administered as an IV infusionover about 60 minutes.Lyophilized powder for IV administration: A sterile preparation can beprepared with (i) 100-1000 mg of the desired compound of this inventionas a lypholized powder, (ii) 32-327 mg/mL sodium citrate, and (iii)300-3000 mg Dextran 40. The formulation is reconstituted with sterile,injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL,which is further diluted with saline or dextrose 5% to 0.2-0.4 mg/mL,and is administered either IV bolus or by IV infusion over 15-60minutes.Intramuscular suspension: The following solution or suspension can beprepared, for intramuscular injection:50 mg/mL of the desired, water-insoluble compound of this invention5 mg/mL sodium carboxymethylcellulose4 mg/mL TWEEN 809 mg/mL sodium chloride9 mg/mL benzyl alcoholHard Shell Capsules: A large number of unit capsules are prepared byfilling standard two-piece hard galantine capsules each with 100 mg ofpowdered active agent, 150 mg of lactose, 50 mg of cellulose and 6 mg ofmagnesium stearate.Soft Gelatin Capsules: A mixture of active agent in a digestible oilsuch as soybean oil, cottonseed oil or olive oil is prepared andinjected by means of a positive displacement pump into molten gelatin toform soft gelatin capsules containing 100 mg of the active agent. Thecapsules are washed and dried. The active agent can be dissolved in amixture of polyethylene glycol, glycerin and sorbitol to prepare a watermiscible medicine mix.Tablets: A large number of tablets are prepared by conventionalprocedures so that the dosage unit is 100 mg of active agent, 0.2 mg. ofcolloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose.Appropriate aqueous and non-aqueous coatings may be applied to increasepalatability, improve elegance and stability or delay absorption.Immediate Release Tablets/Capsules: These are solid oral dosage formsmade by conventional and novel processes. These units are taken orallywithout water for immediate dissolution and delivery of the medication.The active agent is mixed in a liquid containing ingredient such assugar, gelatin, pectin and sweeteners. These liquids are solidified intosolid tablets or caplets by freeze drying and solid state extractiontechniques. The drug compounds may be compressed with viscoelastic andthermoelastic sugars and polymers or effervescent components to produceporous matrices intended for immediate release, without the need ofwater.Method of Treating Non-Hodgkin's Lymphoma (NHL), Particularly 1st Line,2nd Line, Relapsed, Refractory, Indolent or Aggressive Non-Hodgkin'sLymphoma (NHL), in Particular Follicular Lymphoma (FL), ChronicLymphocytic Leukaemia (CLL), Marginal Zone Lymphoma (MZL), Diffuse LargeB-Cell Lymphoma (DLBCL), Mantle Cell Lymphoma (MCL), TransformedLymphoma (TL), or Peripheral T-Cell Lymphoma (PTCL)

The present invention also relates to a method of treating orprophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st line, 2ndline, relapsed, refractory, indolent or aggressive non-Hodgkin'slymphoma (NHL), in particular follicular lymphoma (FL), chroniclymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse largeB-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformedlymphoma (TL), or peripheral T-cell lymphoma (PTCL), in a mammal, saidmethod comprising administering a 2,3-dihydroimidazo[1,2-c]quinazolinecompound as defined herein, or a pharmaceutical composition containingsame, as a sole active agent, or administering a combination of a) saidcompound or a pharmaceutical composition containing said compound and b)one or more further active agents as defined herein.

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer isnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL).

The embodiments of the methods of treating or prophylaxis of cancer,e.g. non-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line,relapsed, refractory, indolent or aggressive non-Hodgkin's lymphoma(NHL), in particular follicular lymphoma (FL), chronic lymphocyticleukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-celllymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (IL),or peripheral T-cell lymphoma (PTCL), as defined supra, are as describedin the embodiments of the use of the compounds/combinations, asdescribed supra.

The present invention relates to a method for using the compounds of thepresent invention and compositions thereof, to treat mammaliannon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL). Compounds can be utilized to inhibit,block, reduce, decrease, etc., cell proliferation and/or cell division,and/or produce apoptosis, in the treatment or prophylaxis ofnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL). This method comprises administeringto a mammal in need thereof, including a human, an amount of a compoundor combination of this invention, or a pharmaceutically acceptable salt,isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc.which is effective for the treatment or prophylaxis of non-Hodgkin'slymphoma (NHL), particularly 1st line, 2nd line, relapsed, refractory,indolent or aggressive non-Hodgkin's lymphoma (NHL), in particularfollicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginalzone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle celllymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma(PTCL).

This disorder has been well characterized in humans, but also existswith a similar etiology in other mammals, and they can be treated byadministering pharmaceutical compositions of the present invention.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of, etc., of a disease or disorder, such as a carcinoma.

Dose and Administration

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment or prophylaxis of non-Hodgkin's lymphoma (NHL),particularly 1st line, 2nd line, relapsed, refractory, indolent oraggressive non-Hodgkin's lymphoma (NHL), in particular follicularlymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zonelymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle celllymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma(PTCL), by standard toxicity tests and by standard pharmacologicalassays for the determination of treatment of the conditions identifiedabove in mammals, and by comparison of these results with the results ofknown medicaments that are used to treat these conditions, the effectivedosage of the compounds of this invention can readily be determined fortreatment of the indication. The amount of the active agent to beadministered in the treatment of the condition can vary widely accordingto such considerations as the particular compound and dosage unitemployed, the mode of administration, the period of treatment, the ageand sex of the patient treated, and the nature and extent of thecondition treated.

The total amount of the active agent to be administered will generallyrange from about 0.001 mg/kg to about 200 mg/kg body weight per day, andpreferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.Clinically useful dosing schedules will range from one to three times aday dosing to once every four weeks dosing. In addition, “drug holidays”in which a patient is not dosed with a drug for a certain period oftime, may be beneficial to the overall balance between pharmacologicaleffect and tolerability. A unit dosage may contain from about 0.5 mg toabout 1,500 mg of active agent, and can be administered one or moretimes per day or less than once a day. The average daily dosage foradministration by injection, including intravenous, intramuscular,subcutaneous and parenteral injections, and use of infusion techniqueswill preferably be from 0.01 to 200 mg/kg of total body weight. Theaverage daily rectal dosage regimen will preferably be from 0.01 to 200mg/kg of total body weight. The average daily vaginal dosage regimenwill preferably be from 0.01 to 200 mg/kg of total body weight. Theaverage daily topical dosage regimen will preferably be from 0.1 to 200mg administered between one to four times daily. The transdermalconcentration will preferably be that required to maintain a daily doseof from 0.01 to 200 mg/kg. The average daily inhalation dosage regimenwill preferably be from 0.01 to 100 mg/kg of total body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

Biomarkers:

Biomarkers used for patient stratification are e.g. the expression ofPI3K isoforms, BTK and IKK, BCR activation, BCR downstream activation ofNFκB pathway, c-Myc, EZH2, for predicting the sensitivity and/orresistance of a cancer patient to said compound, thus providingrationale-based synergistic combination as defined herein to overcomethe resistance.

Compounds Used

Throughout the whole of this text, including in the Examples whichfollow:

1. “compound of formula l” refers to2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,of structure:

or a solvate, hydrate or stereoisomer thereof.2. “compound A” refers to2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamidedihydrochloride, of structure:

or a solvate, hydrate or stereoisomer thereof.

The synthesis of compound A is described in European patent applicationnumber EP 11 161 111.7, and in PCT application number PCT/EP2012/055600published under WO 2012/136553, both of which are hereby incorporatedherein in their entirety by reference.

Synthesis of Compound A:

To a suspension of the compound of formula I (400 g) in water (1.1 L) atroom temperature was added a 32% aqueous 32% (aqueous) hydrochloric acidsolution is with stirring dosed at room temperature to a suspension of400 g of the compound of formula (I) in 1.1 L water until a pH of 3-4 iswas reached. Additional 90 mL water (90 mL) and 32% hydrochloric acidare were added until a pH of 1.8 to 2.0 is was attained. E160 mL ethanol(160 mL) are dosed into was added to the mixture, followed by seedcrystals. After stirring for 30 minutes, 1740 g additional ethanol (2.2L) are dosed within 5 h was added into the mixture over 5 h, which isand the resulting mixture was subsequently stirred for 1 h. Thesuspension is filtered and the residue is washed first with a mixture of130 g water and 215 g ethanol, secondly with a mixture of 80 g water and255 g ethanol and then with 320 g pure ethanol. The filter cake is driedat 40° C. under vacuum to yield 457 g product (99% of theory).

Characterization of Compound A:

The chemical structure of compound A has been confirmed using thedescribed methods of structural analysis.

IR and Raman Spectroscope Apparatus and Measuring Conditions

FT-IR/FT-Raman-Spectrometer Bruker IFS 66 v/Bruker RFS 100 Spectralresolution 2 cm⁻¹/2 cm⁻¹ Number of interferograms 32/64 Wave numberrange 4000-500 cm⁻¹/3500-100 cm⁻¹ Laser power -/350 mW Samplepreparation KBr pellet/solid in test tube

Assignment of the Characteristic Bands

Table: Assignment of the characteristic active vibrations to thespectrum with ν≡stretching vibrations; δ≡bending vibrations; o.o.p.≡outof plane.

IR Band Raman Band Assigned Structure position [cm⁻¹] position [cm⁻¹] νN—H 3336 — ν ═C—H 3176 3090 ν C—H 2942 2990-2963 ν NH⁺ 2687-2474 — νAmide I 1669 1664 ν C═C, ν C═N, δ N—H, Amide II 1618-1477 1619-1476 νC—O 1285 1291 δ ═C—H o.o.p. 812 — ν ≡ stretching vibrations; δ ≡ bendingvibrations; o.o.p. ≡ out of plane

The IR spectrum is given in FIG. 7.

The Raman spectrum is given in FIG. 8.

UV/VIS Spectroscopy Apparatus and Measuring Conditions

UV/VIS spectrometer Varian Cary 4 Cuvette Quartz, 1 cm Wave number range200-800 nm Sample preparation 4.67 mg/500 mL water Bands 309 nm

The UV/vis spectrum is given in FIG. 9.

NMR Spectroscopy ¹H-NMR-Spectroscopy Equipment and ExperimentalParameters:

NMR spectrometer Bruker, model Avance Working frequency 500.13 MHzSolvent Dimethylsulfoxide (DMSO-d6) Internal reference compoundTetramethylsilane (TMS) Concentration 3.08 mg/mL solution Diameter ofsample tube 5 mm Temperature approx. 25° C. Technique Fourier transformmode Spectral width 20.65 ppm Digital resolution 0.079 Hz/Pt Pulselength 4.5 μsec, 30° Pulse flip angle Acquisition time 6.34 secRelaxation time 0.5 sec No. of free induction decays 32

Structural Formula for the Assignment of NMR Signals

Chemical Shift, Signal Multiplicity, Relative Number of Nuclei:

Chemical shift Multiplicity and no. of nuclei H-atoms(a) δ (ppm)coupling constants(b) H/molecule H-26 2.32 M 2 H-29; H-33 3.11; 3.48 M;M 2; 2 H-30; H-32 3.83; 3.98 M; M 2; 2 H-27 3.29 M 2 —OCH₃ 4.00 S 3 H-254.37 T 2 H-2; H-3 4.47; 4.19 T; T 2; 2 H-9 7.39 D 1 NH₂ 7.54 S 2 H-108.21 D 1 H-16; H-20 8.97 S 1; 1 HCl 11.1; 12.6 bS; bS 1; 1 H-12 13.4 bS1 (a)Numbering refers to the structural formula for the assignment ofNMR-signals. (b)S = Singlet bS = broad Singlet D = Doublet T = Triplet M= Multiplet

The ¹H-NMR Spectrum of compound A is given in FIG. 10.

¹³C-NMR-Spectroscopy Equipment and Experimental Parameters

NMR spectrometer Bruker, model Avance Working frequency 125.76 MHzSolvent Dimethylsulfoxide-d₆ (DMSO) Internal reference compoundTetramethylsilane (TMS) Concentration 37.2 mg/mL solution Diameter ofsample tube 5 mm Temperature approx. 27° C. Technique Fourier transformmode Spectral width 240.95 ppm Digital resolution 0.4624 Hz/Pt Pulselength 11.0 μsec, 90° Pulse flip angle Acquisition time 1.08 secRelaxation time 4 sec No. of free induction decays 256Chemical Shift, Signal Multiplicity, Rel. No. of Nuclei:

Chemical shift Multiplicity and no. of nuclei C-atoms(a) δ (ppm)coupling constants(b) C/molecule C-26 22.73 T 1 C-2; C-3 44.96; 45.65 T;T 1; 1 C-29; C-33 50.84 T 1; 1 C-27 53.01 T 1 OCH₃ 61.24 Q 1 C-30; C-3263.03 T 1; 1 C-25 66.81 T 1 C-10a 100.79 S 1 C-9 112.17 D 1 C-15 118.16S 1 C-10 123.86 D 1 C-6a 132.43 S 1 C-7 133.95 S 1 C-5 148.58 S 1 C-11156.29 S 1 C-8 156.89 S 1 C-16; C-20 160.20 D 1; 1 C-18 164.61 S 1 C═O175.65 S 1 (a)Numbering refers to the structural formula for theassignment of NMR-signals. (b)S = Single (C) D = Doublet (CH) T =Triplet (CH₂) Q = Quadruplet (CH₃)

The ¹³C-NMR Spectra of compound A are given in FIGS. 11 and 12.

Mass Spectrometry Instrumental Parameters

Mass spectrometer Waters ZQ Ionization mode ESI(Electrospray-Ionization) Solvent CH₃CN/H₂O

Interpretation of the Spectrum

Mass value (m/z) Rel. Intensity (%) Ion Formation 481.2 46 (M + H)⁺354.1 5 (C16 H16 N7 O3)⁺ 261.7 26 (M + 2H + CH₃CN)⁺² 241.2 100 (M +2H)⁺²

The Mass Spectrum of compound A is given in FIG. 13. Refer to thespectrum for relative peak intensities.

Elemental Analysis

Elemental analysis was conducted by Bayer Industry Services, Leverkusen,Germany.

Results

Calculated including 7.0% Measured Calculated water Element [%] [%] [%]Difference C 47.5 49.9 46.4 1.1 H 5.7 5.5 5.9 0.2 N 19.1 20.3 18.8 0.3 O18.1 11.6 17.0 1.1 Cl 11.9 12.8 11.9 0.0 Sum 102.3 100.1 100.0 —

The elemental analysis is consistent with compound A with 7% water.

Further Method of Preparation of Compound “A”

To a suspension of 366 g of compound of formula (I) in 1015 g water, 183g of an aqueous hydrochloric acid solution (32%) were added whilemaintaining the temperature at 20° C.). (+-2° until a pH of 3 to 4 wasreached. The resulting mixture was stirred at room temperature for morethan 10 min. filtered and the filtercake washed with additional 82 g ofwater. The filtrate was adjusted to pH 1.8 to 2.0 using aqueoushydrochloric acid solution (32%). The mixture was stirred for 10 min. atroom temperature, 146 g of ethanol (100%) were added and stirred foranother 10 min. 1 g of seed crystals were added, followed by 1592 gethanol within 5 h. The resulting substance was removed by filtration,washed with a water-ethanol mixture and dried in vacuo to give 410 g(97%) of compound A of a purity>99% according to HPLC.

2. “PI3Kδ-selective inhibitor GS-1101” refers to PI3Kδ-selectiveinhibitor CAL-101 (GS-1101), was purchased from ChemieTec and is ofstructure shown below:

3. “BTK inhibitor ibrutinib” refers to the BTK inhibitor Ibrutinib(PCI32765), which was purchased from enamine and is of structure shownbelow:

4. “IKK inhibitor BAY Compound B” is the free base (−)-S-enantiomerunder Example 2 of PCT application published under WO 2003/076447 and isof structure:

EXAMPLES

The invention is demonstrated in the following examples which are notmeant to limit the invention in any way:

Mutation and Protein Expression Analysis of DLBCL Cell Lines

TABLE 1 Genetic characteristics of DLBCL cell lines ABC-DLBCL GCB-DLBCLSubtype OCI- OCI- SU- SU- SU-DHL- SU-DHL- Mutation HBL-1 TMD-8 Ly3 Ly19DHL-4 DHL-5 8 10 CD79 mut mut WT WT WT WT WT WT MyD88 mut WT mut WT WTWT WT WT CARD11 WT WT mut WT WT WT WT WT EZH2 WT WT WT WT mut WT WT mutBcl2 mut WT mut Mut mut WT WT mut c-Myc WT WT WT WT WT WT mut mut ABC,activated B-cell-like; GCB, germinal B-cell-like; mut, mutant

Example 1 FIG. 1 Shows Signaling Pathways Downstream of Receptors onB-Cells. (See Reference 5A)

-   -   COMPOUND A demonstrated 6/6 PR in follicular NHL with partial        response observed at the end of cycle 2 at doses 0.8 mg/kg        except in one case where the PR was reached at the end of cycle        4 at 0.6 mg/kg.    -   In contrast to PI3Kdelta-selective inhibitor GS-1101 (9/9 PD in        DLBCL patients), 1/3 SD with 39% tumor reduction was observed in        DLBCL patients.

Example 2 FIG. 2 Shows Activity of COMPOUND A in NHL Patients

Initial clinical efficacy of the pan-PI3K inhibitor COMPOUND A in NHL(see reference 6A) PD, progression of disease; PR, partial response; SD,stable disease; WT, wild type for PIK3CA.

-   -   COMPOUND A demonstrated 6/6 PR in follicular NHL with partial        response observed at the end of cycle 2 at doses 0.8 mg/kg        except in one case where the PR was reached at the end of cycle        4 at 0.6 mg/kg.    -   In contrast to PI3Kdelta-selective inhibitor GS-1101 (9/9 PD in        DLBCL patients), 1/3 SD with 39% tumor reduction was observed in        DLBCL patients.

Example 3 FIG. 3 Shows Differential Expression of PI3K Isoforms, BTK,and IKK in DLBCL Cell Lines Methods:

The mutation status was obtained from public database. Proteinexpression was analyzed by western blot with antibodies against PI3Kp110α (#4249, Cell Signaling); PI3K p1100 (#3011, Cell Signaling) PI3Kp110γ (#5405, Cell Signaling), PI3K p110δ (#ab1678, Abcam), BTK (#3533,Cell Signaling), IKKβ (#2370, Cell Signaling).

Conclusions

The expression of PI3Kα, PI3Ki3, and PI3Kγ isoforms was similar in all 8DLBCL cell lines tested, while the expression of PI3Kδ varied

-   -   IKKβ was expressed across all DLBCL cell lines, while BTK was        selectively expressed

Example 4 Anti-Proliferative Activity of PI3K, BTK, and IKK Inhibitorsin DLBCL Cell Lines

FIG. 4 shows differential anti-proliferative profile of pan-PI3Kinhibitor COMPOUND A, PI3Kδ-selective inhibitor GS-1101, BTK inhibitoribrutinib, and IKK inhibitor BAY compound B in DLBCL cell lines*>1.0E-05 (M)

Method: Anti-proliferative effects were assessed by a 72-hCellTiter-Glo* assay (Promega, Cat.#G7573). Briefly, cells were platedat 250-2000 cells/well of 384-well plates (based on cell lines) in 20 μLof growth medium. For each cell line assayed, cells were plated into aseparate plate for determination of luminescence at the t=0 hours andt=72 hour time points. Following overnight incubation at 37° C.,luminescence values for the t=0 samples were determined by adding 20 μLof Cell Titer-Glo solution per well, transferring the plates to anorbital shaker for 10 minutes at room temperature, and then reading theplates on a Wallac Victor2 1420 Multilabel HIS Counter using theluminometry window (maximum light detection is measured at 428 nM). Doseplates for t=72 hour time points were treated with compounds dilutedinto growth medium in a final volume of 30 μL. Cells were then incubatedfor 72 hours at 37° C. Luminescence values for the t=72 hour sampleswere determined by adding 30 μL of Promega CellTiter-Glo solution,placing the cells on a shaker for 10 minutes at room temperature, andthen reading the luminescence using a Victor luminometer. For dataprocessing, t=0 values are subtracted from those determined for the t=72hour time points, for both the treated and untreated samples. Percentdifferences in luminescence between drug treated and controls are usedto determine percent inhibition of growth.

Conclusions:

Overall, the potent activity of PI3K, BTK, and IKK inhibitors in asubset of cell lines correlated with the high expression of the targets

-   -   Pan-PI3K inhibitor COMPOUND A was particularly active in the        cells with activated BCR signaling (TMD-8 and HBL-1). It was        also effective in DLBCL cells with activating NFκB pathway        (HBL-1 and OCI-Ly3), but required higher concentrations to reach        complete tumor growth inhibition (assessed by IC₉₀), indicating        that combination treatment might be needed to induce tumor        stasis and tumor regression    -   PI3Kδ-selective inhibitor GS-1101 was active only in BCR-mutant        cell lines without downstream mutations. Any mutations        downstream of BCR led to >100-fold decreased activity with        respect to IC₅₀ values    -   BTK inhibitor ibrutinib was active in BCR-mutant cell lines even        in the presence of activating NFκB pathway (IC₅₀<30 nM). Cell        lines without BCR-activating mutations showed a dramatically        increased IC₅₀ value (>1 μM) or complete inactivity    -   IKKβ inhibitor BAY compound B was more active in ABC-DLBCL        compared with GCB-DLBCL cell lines

Example 5 In Vivo Efficacy of COMPOUND a and Ibrutinib in TMD-8Xenograft Model in CB17 scid Mice Methods:

Untreated female 5-6 week old CB17.Scid mice are inoculated with 10×10⁶TMD-8 tumor cells (suspended in 50% Matrigel and 50% Medium)subcutaneously into the flank. Animals are randomized to treatmentgroups when tumors reach a tumor area of 30-35 mm². Treatment isconducted as described in FIG. 5 legend. Tumor area and animal body arerecorded three times per week.

Conclusions:

PI3K inhibitor compound A achieved good tumor growth inhibition in theTMD-8 model upon treatment with 14 mg/kg every 2 days, reaching TGI(tumor growth inhibition) based on relative tumor area (_(rel TA)) atthe end of the study of 75%. BTK inhibitor ibrutinib did also show goodtumor growth inhibition in TMD-8 tumors upon treatment with 20 mg/kgonce daily, reaching TGI (rel TA) of 70%. All treatments were welltolerated.

Overall, PI3K inhibitor COMPOUND A shows potent anti-tumor activity inthe human ABC-DLBCL model TMD-8, comparable to BTK inhibitor ibrutinib.

See FIG. 5. Effect of COMPOUND A and ibrutinib on tumor growth in vivo.COMPOUND A was administered iv once every 2 days (Q2D) at 10 and 14mg/kg and ibrutinib was dosed po at 12 and 20 mg/kg. Tumor growth wasmonitored by determination of the tumor area using caliper measurement 3times weekly. QD, once daily; SD, standard deviation of the mean; TGI,relative tumor growth inhibition vs control (%, tumor area at the end ofthe study on day 29)

Example 6 Combination Effects of PI3K Inhibitor with BTK, IKK, and MEKInhibitors in DLBCL Cells Methods: Combination Study:

The combination effects were evaluated using combination indexisobologram analysis. The efficacy parameters were the median effect ina 72-hour cell proliferation assay. Briefly, cells were plated in384-well plate with 25 μl medium. After 24 hours, 5 μL of experimentalmedia containing either compound A (D1), or combination partner D2(Ibrutinib, BAY Compound B, or REFAMETINIB (BAY 86-9766 (RDEA-119))), orthe combination of compound A plus D2 at different ratios(0.8×D1+0.2×D2, 0.6×D1+0.4×D2, 0.4×D1+0.6×D2, 0.2×D1+0.8×D2,0.1×D1+0.9×D2) were used to make serial three-fold dilutions to generate7-dose curves. Experiments were conducted in triplicates. The mappingEC₉₀/1C₉₀ and EC₉₀/IC₉₀ were calculated using Analyze5 computer program.The corresponding component doses of D1 and D2 at the E(|)C90/E(I)C90were calculated and used for plotting isobolograms. Multiple drug effectwas analyzed as described by Chou (see reference 7A) and the combinationindex was calculated using the formula:

Combination Index=[D1x]/D1′+[D2x]/D2′

[D1x] and [D2x] refer to the Drug 1 and Drug 2 concentration atEC₅₀/IC₅₀ or EC₉₀/IC₉₀, respectively, in combination D1′ and D2′ referto the EC₅₀/IC₅₀ or EC₉₀/IC₉₀ values of D1 and D2, respectively, as asingle agent. In this analysis, values less than 1.0 indicatesynergistic interactions, values greater than 1.0 indicate antagonisticinteractions, and values around 1.0 indicate additive interactions.

Western Blot:

Modulation of intracellular pathways were assessed by Western blots at24h post treatment with indicated compounds either as single agent or incombination. Antibodies used in this study are AKT (#4685, CellSignaling), p-AKT (04060, Cell Signaling), ERK (#4695, Cell Signaling),p-ERK (#4376, Cell Signaling), BTK (#3533, Cell Signaling), p-BTK(05082, Cell Signaling), IκBα (#4812, Cell Signaling), p-IκBα (#AF4809,R&D), p-IKKα/β (02078, Cell Signaling), IKKβ (02370, Cell Signaling).

Conclusions:

Combination of pan-PI3K inhibitor compound A with BTK inhibitoribrutinib:

-   -   Synergistic antitumor effect observed in the tumor cell lines        responding to BTK inhibition    -   Antagonistic effect observed in BTK inhibitor-resistant tumor        cell lines    -   No synergistic effects on complete tumor growth inhibition in        the cell lines with activated NFκβ pathway (MyD88 or CARD11        mutation), even in the presence of BCR activation    -   Combination of pan-PI3K inhibitor COMPOUND A with IKK inhibitor        BAY Compound B:        -   Synergistic antitumor effect observed in ABC-DLBCL cells        -   In GCB-DLBCL cells, the combination had both moderate            synergistic and antagonistic effects    -   Feedback activations by inhibition of PI3Kδ, BTK, and IKK:        -   Activation of p-ERK by BTK inhibitor ibrutinib in both HBL-1            and OCI-Ly3 cells        -   Activation of p-IKKα/13 by IKK inhibitor BAY Compound B in            both HBL-1 and OCI-Ly3 cells        -   Activation of p-ERK by PI3Kδ inhibitor GS-1101 in HBL-1            cells    -   Very strong synergistic combination with the MEK inhibitor        REFAMETINIB (BAY 86-9766 (RDEA-119)) was demonstrated in MyD88-        and CARD11-mutant OCI-Ly3 DLBCL cell lines

FIG. 6 shows the combination effect of PI3K inhibitor compound A withBTK inhibitor ibrutinib or IKK inhibitor BAY Compound B in DLBCL celllines

FIG. 6A shows the anti-proliferative effect was investigated using a72-h CellTiter-Glo′ assay. The results were analyzed as previouslydescribed (see reference 7A). Each combination study was conducted with5 different concentration ratios of 2 compounds and IC₅₀ values weredetermined using a series of 7-dose dilution. The differentialcombination effects of BTK vs IKK inhibitor were further investigated byanalyzing the modulation of signaling pathways using Western blots withindicated anti-phospho and anti-total target proteins in OCI-Ly3 (FIG.6B) and HBL-1 (FIG. 6C) cells. FIG. 6D shows the strong synergisticcombination with MEK inhibitor REFAMETINIB (BAY 86-9766 (RDEA-119)) inMyD88- and CARD11-mutant OCI-Ly3 DLBCL cells CI, combination index; NA,not achievable at a concentration of 10 μM of the 2 compounds.

Example 7 Phase II Study of Single Agent COMPOUND OF FORMULA I inPatients with 1st Line, 2nd Line, Relapsed, Refractory, Indolent orAggressive Lymphoma

A phase I dose-escalation study (Patnaik et al, ASH 2012) establishedthe maximum tolerated dose of COMPOUND OF FORMULA I (0.8 mg/kg) andreported promising activity (6/6 PR) in follicular lymphoma. In thepresent study we further investigated the activity and safety ofCOMPOUND OF FORMULA I in patients with indolent or aggressive lymphomasubtypes that have progressed after standard therapy.

In this Phase II study, patients with histologically confirmed indolentor aggressive lymphoma relapsed or refractory to prior lines oftreatment were eligible. Patients received COMPOUND OF FORMULA I at adose of 0.8 mg/kg as a 1 hour infusion on days 1, 8 and 15 of a 28-daycycle. Patients continued on therapy until disease progression orunacceptable toxicity. Responses were assessed every two cyclesaccording to the response criteria for lymphoma (Cheson et al, JCO17:1244, 1999) or the guidelines for diagnosis and treatment of chroniclymphocytic leukemia (CLL; Hallek et al., Blood 111:5446-56, 2008).

Results:

As of May 31, 2013, a total of 61 lymphoma patients (27 indolent and 34aggressive) were enrolled and 56 started study treatment. Patients weresimilarly distributed among indolent and aggressive cohorts with respectto gender (52% female), median age (68 yr, range 22-90) and ethnicity(76% Caucasian) and were heavily pretreated (median number of priortherapies: 3; prior Rituximab: 84%; prior ASCT: 20%). Othercharacteristics included advanced stage III-IV in 85% and B symptoms in17%. The following entities were represented: follicular (FL; n=13); CLL(n=11); marginal zone (MZL; n=3; none re-staged); diffuse large B-cell(DLBCL; n=17); mantle cell (MCL; n=7); transformed (n=5); and peripheralT-cell (PTCL; n=4). At the time of analysis patients had receivedbetween 1 and 5 cycles of treatment. Objective responses were seenacross histologic subtypes (Table 1). At the time of this interimanalysis, the overall response rate (RR) and complete RR were 44% and22% in FL, 83% and 17% in MCL, and 50% and 0% in PTCL, respectively.

TABLE 1 Best response by lymphoma subtype in staged patients FL CLLDLBCL MCL Transformed PTCL (n = 9) (n = 9) (n = 17) (n = 6) (n = 5) (n =4) CR/CRu 2 0 0 1 0 0 PR 2 4 2 4 1 2 SD 5 4 7 0 2 0 PD 0 1 8 1 2 2CR—complete response; CRu—CR unconfirmed; PR—partial response; SD—stabledisease; PD—progressive disease

Grade 3 adverse events (AE) were reported in 49% of patients, and grade4 AE (all neutropenia) occurred in 15% of patients. Grade 3/4 AEsoccurring in 5% of patients included hypertension (31%), neutropenia(16%), hyperglycemia (13%), diarrhea (5%) and fatigue (5%).Hyperglycemia of any grade occurred in 47%. Four patients requiredinsulin therapy, but no grade 4 hyperglycemia was observed. Hypertensionof any grade occurred in 46% of patients. Eight patients requiredantihypertensive treatment, but no grade 4 hypertension was reported.Diarrhea of any grade occurred in 25% of cases. No case of colitis wasreported. There were two cases of interstitial pneumonitis, with bothcases resolved following corticosteroid administration. Withdrawal ofstudy drug due to AEs occurred in 10 patients (16%), and 4 patientsrequired a dose reduction. Four deaths occurred; 1 due to progressivedisease, 1 due to acute respiratory insufficiency, 1 due to Cryptococcalmeningitis and 1 due to sepsis after start of a salvage chemotherapyregimen.

Conclusions:

The novel PI3K inhibitor COMPOUND OF FORMULA I is clinically active as asingle agent and appears to have an acceptable toxicity profile in 1stline, 2nd line, relapsed, refractory lymphoma. Preliminary efficacyresults are encouraging, as promising activity has been observed in FL,MCL, and PTCL. The safety profile was consistent with prior studies.

SUMMARY

-   -   All 4 PI3K isoforms are expressed in a panel of 8 DLBCL cell        lines    -   The pan-PI3K inhibitor COMPOUND A, P130-selective inhibitor        GS-1101, BTK inhibitor Ibrutinib and IKK inhibitor BAY compound        B demonstrate differential profiles of anti-proliferative        activity        -   Broader and greater antitumor activity is observed with            pan-PI3K inhibitor    -   COMPOUND A compared with PI3Kδ-selective inhibitor GS-1101, BTK        inhibitor ibrutinib, and IKK inhibitor BAY compound B    -   COMPOUND A administered iv Q2D (T_(1/2)˜1 h in mice) at 14 mg/kg        demonstrated marked antitumor activity comparable to Ibrutinib        in CD79 mutant TMD-8 DLBCL xenograft model    -   A cell-specific synergistic effect was observed for COMPOUND A        in combination with an IKK inhibitor, BTK inhibitor, and MEK        inhibitor BAY 86-9766    -   Potential biomarkers to be considered for both monotherapy and        combination therapy:        -   Target expression        -   BCR activation        -   BCR downstream activation of NFκB pathway        -   c-Myc, EZH2    -   Further studies may reveal more effective combination partners        for COMPOUND A

These findings provide a retionale to develop personalized therapies forthe treatment of non-Hodgkin's lymphoma (NHL), particularly 1st line,2nd line, relapsed, refractory, indolent or aggressive non-Hodgkin'slymphoma (NHL), in particular follicular lymphoma (FL), chroniclymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse largeB-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformedlymphoma (TL), or peripheral T-cell lymphoma (PTCL).

Hence, as mentioned supra, the present invention relates to the use ofbiomarkers involved in the modification of the expression of PI3Kisoforms, BTK and IKK, BCR activation, BCR downstream activation of NFκBpathway, c-Myc, EZH2, for predicting the sensitivity and/or resistanceof a patient with non-Hodgkin's lymphoma (NHL), particularly 1st line,2nd line, relapsed, refractory, indolent or aggressive non-Hodgkin'slymphoma (NHL), in particular follicular lymphoma (FL), chroniclymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse largeB-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformedlymphoma (TL), or peripheral T-cell lymphoma (PTCL), to a2,3-dihydroimidazo[1,2-c]quinazoline compound as defined herein, thusproviding retionale-based synergistic combination as defined herein toovercome the resistance.

In accordance with an embodiment, the present invention relates to theuse of biomarkers involved in the modification of the expression of PI3Kisoforms, BTK and IKK, BCR activation, BCR downstream activation of NFκBpathway, c-Myc, EZH2, for predicting the sensitivity and/or resistanceof a patient with non-Hodgkin's lymphoma (NHL), particularly 1st line,2nd line, relapsed, refractory, indolent or aggressive non-Hodgkin'slymphoma (NHL), in particular follicular lymphoma (FL), chroniclymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse largeB-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformedlymphoma (IL), or peripheral T-cell lymphoma (PTCL), to a2,3-dihydroimidazo[1,2-c]quinazoline compound as defined herein, thusproviding a rationale-based synergistic combination as defined herein toovercome the resistance (patient stratification).

In accordance with an embodiment, the present invention relates to amethod of determining the level of a component of one or more of theexpression of PI3K isoforms, BIK and IKK BCR activation, BCR downstreamactivation of NFκB pathway, c-Myc, EZH2.

Further, as mentioned supra, the present invention thus relates tocombinations of:

a) a 2,3-dihydroimidazo[1,2-c]quinazoline compound as defined supra, ora physiologically acceptable salt, solvate, hydrate or stereoisomerthereof; or pharmaceutical compositions containing such a compound or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof;andb) one or more further active agents, in particular an active agentselected from an anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagent, more particularly one or more further active agents selected fromthe group consisting of:

-   -   PI3Kδ-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK        inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766        (RDEA-119)),        as defined supra.

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer isnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), inparticular follicular lymphoma (FL), chronic lymphocytic leukaemia(CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), orperipheral T-cell lymphoma (PTCL).

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer isnon-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed,refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL).

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer is follicularlymphoma (FL).

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer is chroniclymphocytic leukaemia (CLL).

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer is marginalzone lymphoma (MZL).

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer is diffuselarge B-cell lymphoma (DLBCL).

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer is mantlecell lymphoma (MCL).

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer istransformed lymphoma (TL).

In accordance a particular embodiment of any of the above aspects, orembodiments thereof, of the present invention, said cancer is peripheralT-cell lymphoma (PTCL).

REFERENCES

-   1. Abbosh, P. H.; Nephew, K. P. Multiple signaling pathways converge    on b-catenin in thyroid cancer. Thyroid 2005, 15, 551-561.-   2. Ali, I. U.; Schriml, L. M.; Dean, M. Mutational spectra of    PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase    activity. J. Natl. Cancer Inst. 1999, 91, 1922-1932.-   3. Bachman, K. E.; Argani, P.; Samuels, Y.; Silliman, N.; Ptak, J.;    Szabo, S.; Konishi, H.; Karakas, B.; Blair, B. G.; Lin, C.;    Peters, B. A.; Velculescu, V. E.; Park, B. H. The PIK3CA gene is    mutated with high frequency in human breast cancers. Cancer Biol.    Therap. 2004, 3, 772-775.-   4. Bader, A. G.; Kang, S.; Vogt, P. K. Cancer-specific mutations in    PIK3CA are oncogenic in vivo. Proc. Natl. Acad. Sci. U.S.A 2006,    103, 1475-1479.-   5. Barthwal, M. K.; Sathyanarayana, P.; Kundu, C. N.; Rana, B.;    Pradeep, A.; Sharma, C.; Woodgett, J. R.; Rana, A. Negative    Regulation of Mixed Lineage Kinase 3 by Protein Kinase B/AKT Leads    to Cell Survival. J. Biol. Chem. 2003, 278, 3897-3902.-   6. Benistant, C.; Chapuis, H.; Roche, S. A specific function for    phosphatidylinositol 3-kinase a (p85a-p110a) in cell survival and    for phosphatidylinositol 3-kinase b (p85a-p110b) in de novo DNA    synthesis of human colon carcinoma cells. Oncogene 2000, 19,    5083-5090.-   7. Broderick, D. K.; Di, C.; Parrett, T. J.; Samuels, Y. R.;    Cummins, J. M.; McLendon, R. E.; Fults, D. W.; Velculescu, V. E.;    Bigner, D. D.; Yan, H. Mutations of PIK3CA in anaplastic    oligodendrogliomas, high-grade astrocytomas, and medulloblastomas.    Cancer Res. 2004, 64, 5048-5050.-   8. Brown, R. A.; Shepherd, P. R. Growth factor regulation of the    novel class II phosphoinositide 3-kinases. Biochem. Soc. Trans.    2001, 29, 535-537.-   9. Brunet, A.; Bonni, A.; Zigmond, M. J.; Lin, M. Z.; Juo, P.;    Hu, L. S.; Anderson, M. J.; Arden, K. C.; Blenis, J.;    Greenberg, M. E. Akt promotes cell survival by phosphorylating and    inhibiting a Forkhead transcription factor. Cell 1999, 96, 857-868.-   10. Byun, D.-S.; Cho, K.; Ryu, B.-K.; Lee, M.-G.; Park, J.-I.; Chae,    K.-S.; Kim, H.-J.; Chi, S.-G. Frequent monoallelic deletion of PTEN    and its reciprocal association with PIK3CA amplification in gastric    carcinoma. Int. J. Cancer 2003, 104, 318-327.-   11. Campbell, I. G.; Russell, S. E.; Choong, D. Y. H.;    Montgomery, K. G.; Ciavarella, M. L.; Hooi, C. S. F.; Cristiano, B.    E.; Pearson, R. B.; Phillips, W. A. Mutation of the PIK3CA gene in    ovarian and breast cancer. Cancer Res. 2004, 64, 7678-7681.-   12. Cardone, M. H.; Roy, N.; Stennicke, H. R.; Salvesen, G. S.;    Franke, T. F.; Stanbridge, E.; Frisch, S.; Reed, J. C. Regulation of    cell death protease caspase-9 by phosphorylation. Science 1998, 282,    1318-1321.-   13. Chen, Y. L.; Law, P.-Y.; Loh, H. H. Inhibition of PI3K/Akt    signaling: An emerging paradigm for targeted cancer therapy. Curr.    Med. Chem. Anticancer Agents 2005, 5, 575-589.-   14. Ciechomska, I.; Pyrzynska, B.; Kazmierczak, P.; Kaminska, B.    Inhibition of Akt kinase signaling and activation of For head are    indispensable for up-regulation of FasL expression in apoptosis of    glioma cells. Oncogene 2003, 22, 7617-7627.-   15. Cross, D. A. E.; Alessi, D. R.; Cohen, P.; Andjelkovich, M.;    Hemmings, B. A. Inhibition of glycogen synthase kinase-3 by insulin    mediated by protein kinase B. Nature 1995, 378, 785-9.-   16. Cully, M.; You, H.; Levine, A. J.; Mak, T. W. Beyond PTEN    mutations: the PI3K pathway as an integrator of multiple inputs    during tumorigenesis. Nat. Rev. Cancer 2006, 6, 184-192.-   17. Czauderna, F.; Fechtner, M.; Aygun, H.; Arnold, W.; Klippel, A.;    Giese, K.; Kaufmann, J. Functional studies of the PI(3)-kinase    signaling pathway employing synthetic and expressed siRNA. Nucleic    Acids Res. 2003, 31, 670-682.-   18. del Peso, L.; González-Garcia, M.; Page, C.; Herrera, R.;    Nunez, G. Interleukin-3-induced phosphorylation of BAD through the    protein kinase Akt. Science 1997, 278, 687-689.-   19. Diehl, J. A.; Cheng, M.; Roussel, M. F.; Sherr, C. J. Glycogen    synthase kinase-3b regulates cyclin D1 proteolysis and subcellular    localization. Genes Dev. 1998, 12, 3499-3511.-   20. Dijkers, P. F.; Medema, R. H.; Lammers, J.-W. J.; Koenderman,    L.; Coffer, P. J. Expression of the pro-apoptotic Bcl-2 family    member Bim is regulated by the Forkhead transcription factor    FKHR-L1. Curr. Biol. 2000, 10, 1201-1204.-   21. Domin, J.; Waterfield, M. D. Using structure to define the    function of phosphoinositide 3-kinase family members. FEBS Lett.    1997, 410, 91-95.-   22. Downes, C. P.; Gray, A.; Lucocq, J. M. Probing phosphoinositide    functions in signaling and membrane trafficking. Trends Cell Biol.    2005, 15, 259-268.-   23. Figueroa, C.; Tarras, S.; Taylor, J.; Vojtek, A. B. Akt2    negatively regulates assembly of the POSH-MLK-JNK signaling    complex. J. Biol. Chem. 2003, 278, 47922-47927.-   24. Fleming, I. N.; Gray, A.; Downes, C. P. Regulation of the    Rac1-specific exchange factor tiam1 involves both phosphoinositide    3-kinase-dependent and -independent components. Biochem. J. 2000,    351, 173-182.-   25. Funaki, M.; Katagiri, H.; Inukai, K.; Kikuchi, M.; Asano, T.    Structure and function of phosphatidylinositol-3,4 kinase. Cell.    Signal. 2000, 12, 135-142.-   26. Gallia, G. L.; Rand, V.; Siu, I. M.; Eberhart, C. G.; James, C.    D.; Marie, S. K. N.; Oba-Shinjo, S. M.; Carlotti, C. G.;    Caballero, O. L.; Simpson, A. J. G.; Brock, M. V.; Massion, P. P.;    Carson, B. S., Sr.; Riggins, G. J. PIK3CA gene mutations in    pediatric and adult glioblastoma multiforme. Mol. Cancer Res. 2006,    4, 709-714.-   27. Gershtein, E. S.; Shatskaya, V. A.; Ermilova, V. D.;    Kushlinsky, N. E.; Krasil'nikov, M. A. Phosphatidylinositol 3-kinase    expression in human breast cancer. Clin. Chim. Acta 1999, 287,    59-67.-   28. Gottschalk, A. R.; Doan, A.; Nakamura, J. L.; Stokoe, D.;    Haas-Kogan, D. A-Inhibition of phosphatidylinositol 3-kinase causes    increased sensitivity to radiation through a PKB-dependent    mechanism. Int. J. Radiat. Oncol. Biol. Phys. 2005, 63, 1221-1227.-   29. Gupta, A. K.; Cerniglia, G. J.; Mick, R.; Ahmed, M. S.;    Bakanauskas, V. J.; Muschel, R. J.; McKenna, W. G. Radiation    sensitization of human cancer cells in vivo by inhibiting the    activity of PI3K using LY294002. Int. J. Radiat. Oncol. Biol. Phys.    2003, 56, 846-853.-   30. Haas-Kogan, D.; Shalev, N.; Wong, M.; Mills, G.; Yount, G.;    Stokoe, D. Protein kinase B (PKB/Akt) activity is elevated in    glioblastoma cells due to mutation of the tumor suppressor    PTEN/MMAC. Curr. Biol. 1998, 8, 1195-1198.-   31. Hartmann, C.; Bartels, G.; Gehlhaar, C.; Holtkamp, N.; von    Deimling, A. PIK3CA mutations in glioblastoma multiforme. Acta    Neuropathol. 2005, 109, 639-642.-   32. Hennessy, B. T.; Smith, D. L.; Ram, P. T.; Lu, Y.; Mills, G. B.    Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery. Nat. Rev.    Drug Disc. 2005, 4, 988-1004.-   33. Hodgkinson, C. P.; Sale, E. M.; Sale, G. J. Characterization of    PDK2 activity against Protein Kinase B gamma. Biochemistry 2002, 41,    10351-10359.-   34. Hresko, R. C.; Murata, H.; Mueckler, M.    Phosphoinositide-dependent Kinase-2 is a distinct protein kinase    enriched in a novel cytoskeletal fraction associated with adipocyte    plasma membranes. J. Biol. Chem. 2003, 278, 21615-21622.-   35. Huang, C.; Ma, W.-Y.; Dong, Z. Requirement for    phosphatidylinositol 3-kinase in epidermal growth factor-induced    AP-1 transactivation and transformation in JB6 P+ cells. Mol. Cell.    Biol. 1996, 16, 6427-6435.-   36. Hupp, T. R.; Lane, D. P.; Ball, K. L. Strategies for    manipulating the p53 pathway in the treatment of human cancer.    Biochem. J. 2000, 352, 1-17.-   37. Ihle, N. T.; Williams, R.; Chow, S.; Chew, W.; Berggren, M. I.;    Paine-Murrieta, G.; Minion, D. J.; Halter, R. J.; Wipf, P.; Abraham,    R.; Kirkpatrick, L.; Powis, G. Molecular pharmacology and antitumor    activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase    signaling. Mol. Cancer Therap. 2004, 3, 763-772.    38. Ikenoue, T.; Kanai, F.; Hikiba, Y.; Obata, T.; Tanaka, Y.;    Imamura, J.; Ohta, M.; Jazag, A.; Guleng, B.; Tateishi, K.; Asaoka,    Y.; Matsumura, M.; Kawabe, T.; Omata, M. Functional analysis of    PIK3CA gene mutations in human colorectal cancer. Cancer Res. 2005,    65, 4562-4567.-   39. Ishii, N.; Maier, D.; Merlo, A.; Tada, M.; Sawamura, Y.;    Diserens, A.-C.; Van Meir, E. G. Frequent co-alterations of TP53,    p16/CDKN2A, p14ARF, PTEN tumor suppressor genes in human glioma cell    lines. Brain Pathol. 1999, 9, 469-479.-   40. Itoh, T.; Takenawa, T. Phosphoinositide-binding domains.    Functional units for temporal and spatial regulation of    intracellular signaling. Cell. Signal. 2002, 14, 733-743.-   41. Janssen, J. W. G.; Schleithoff, L.; Bartram, C. R.;    Schulz, A. S. An oncogenic fusion product of the    phosphatidylinositol 3-kinase p85b subunit and HUMORF8, a putative    deubiquitinating enzyme. Oncogene 1998, 16, 1767-1772.-   42. Jimenez, C.; Jones, D. R.; Rodriguez-Viciana, P.;    Gonzalez-Garcia, A.; Leonardo, E.; Wennstrom, S.; Von Kobbe, C.;    Toran, J. L.; R.-Borlado, L.; Calvo, V.; Copin, S. G.; Albar, J. P.;    Gaspar, M. L.; Diez, E.; Marcos, M. A. R.; Downward, J.; Martinez-A,    C.; Merida, I.; Carrera, A. C. Identification and characterization    of a new oncogene derived from the regulatory subunit of    phosphoinositide 3-kinase. EMBO J. 1998, 17, 743-753.-   43. Jucker, M.; Sudel, K.; Horn, S.; Sickel, M.; Wegner, W.;    Fiedler, W.; Feldman, R. A. Expression of a mutated form of the p85a    regulatory subunit of phosphatidylinositol 3-kinase in a Hodgkin's    lymphoma-derived cell line (CO). Leukemia 2002, 16, 894-901.-   44. Kang, S.; Bader, A. G.; Vogt, P. K. Phosphatidylinositol    3-kinase mutations identified in human cancer are oncogenic. Proc.    Natl. Acad. Sci. U.S.A 2005, 102, 802-807.-   45. Kang, S.; Denley, A.; Vanhaesebroeck, B.; Vogt, P. K. Oncogenic    transformation induced by the p110b, -g, and -d isoforms of class I    phosphoinositide 3-kinase. Proc. Natl. Acad. Sci. U.S.A 2006, 103,    1289-1294.-   46. Katso, R.; Okkenhaug, K.; Ahmadi, K.; White, S.; Timms, J.;    Waterfield, M. D. Cellular function of phosphoinositide 3-kinases:    implications for development, immunity, homeostasis, and cancer.    Annu. Rev. Cell Dev. Biol. 2001, 17, 615-675.-   47. Kim, A. H.; Khursigara, G.; Sun, X.; Franke, T. F.; Chao, M. V.    Akt phosphorylates and negatively regulates apoptosis    signal-regulating kinase 1. Mol. Cell. Biol. 2001, 21, 893-901.-   48. Kim, D.; Dan, H. C.; Park, S.; Yang, L.; Liu, Q.; Kaneko, S.;    Ning, J.; He, L.; Yang, H.; Sun, M.; Nicosia, S. V.; Cheng, J. Q.    AKT/PKB signaling mechanisms in cancer and chemoresistance. Front.    Biosci. 2005, 10, 975-987.-   49. Klippel, A.; Kavanaugh, W. M.; Pot, D.; Williams, L. T. A    specific product of phosphatidylinositol 3-kinase directly activates    the protein kinase Akt through its pleckstrin homology domain. Mol.    Cell. Biol. 1997, 17, 338-44.-   50. Kodaki, T.; Woscholski, R.; Hallberg, B.; Rodriguez-Viciana, P.;    Downward, J.; Parker, P. J. The activation of phosphatidylinositol    3-kinase by Ras. Curr. Biol. 1994, 4, 798-806.-   51. Kops, G. J. P. L.; De Ruiter, N. D.; De Vries-Smits, A. M. M.;    Powell, D. R.; Bos, J. L.; Burgering, B. M. T. Direct control of the    Forkhead transcription factor AFX by protein kinase B. Nature 1999,    398, 630-634.-   52. Lee, J. T., Jr.; Steelman, L. S.; McCubrey, J. A.    Phosphatidylinositol 3′-Kinase Activation Leads to Multidrug    Resistance Protein-1 Expression and Subsequent Chemoresistance in    Advanced Prostate Cancer Cells. Cancer Res. 2004, 64, 8397-8404.-   53. Lee, J. W.; Soung, Y. H.; Kim, S. Y.; Lee, H. W.; Park, W. S.;    Nam, S. W.; Kim, S. H.; Lee, J. Y.; Yoo, N. J.; Lee, S. H. PIK3CA    gene is frequently mutated in breast carcinomas and hepatocellular    carcinomas. Oncogene 2005, 24, 1477-1480.-   54. Lemmon, M. A. Phosphoinositide recognition domains. Traffic    2003, 4, 201-213.-   55. Levine, D. A.; Bogomolniy, F.; Yee, C. J.; Lash, A.; Barakat, R.    R.; Borgen, P. I.; Boyd, J. Frequent Mutation of the PIK3CA Gene in    Ovarian and Breast Cancers. Clin. Cancer Res. 2005, 11, 2875-2878.-   56. Li, J.; Yen, C.; Liaw, D.; Podsypanina, K.; Bose, S.; Wang, S.    I.; Puc, J.; Miliaresis, C.; Rodgers, L.; McCombie, R.; Bigner, S.    H.; Giovanella, B. C.; Ittmann, M.; Tycko, B.; Hibshoosh, H.;    Wigler, M. H.; Parsons, R. PTEN, a putative protein tyrosine    phosphatase gene mutated in human brain, breast, and prostate    cancer. Science 1997, 275, 1943-1947.-   57. Li, V. S. W.; Wong, C. W.; Chan, T. L.; Chan, A. S. W.; Zhao,    W.; Chu, K.-M.; So, S.; Chen, X.; Yuen, S. T.; Leung, S. Y.    Mutations of PIK3CA in gastric adenocarcinoma. BMC Cancer 2005, 5,    29.-   58. Liao, Y.; Hung, M.-C. Regulation of the activity of p38    mitogen-activated protein kinase by Akt in cancer and adenoviral    protein E1A-mediated sensitization to apoptosis. Mol. Cell. Biol.    2003, 23, 6836-6848.-   59. Lopez-llasaca, M.; Li, W.; Uren, A.; Yu, J.-c.; Kazlauskas, A.;    Gutkind, J. S.; Heidaran, M. A. Requirement of    phosphatidylinositol-3 kinase for activation of JNK/SAPKs by PDGF.    Biochem. Biophys. Res. Commun. 1997, 232, 273-277.-   60. Ma, Y.-Y.; Wei, S.-J.; Lin, Y.-C.; Lung, J.-C.; Chang, T.-C.;    Whang-Peng, J.; Liu, J. M.; Yang, D.-M.; Yang, W. K.; Shen, C.-Y.    PIK3CA as an oncogene in cervical cancer. Oncogene 2000, 19,    2739-2744.-   61. Mayo, L. D.; Dixon, J. E.; Durden, D. L.; Tonks, N. K.;    Donner, D. B. PTEN protects p53 from Mdm2 and sensitizes cancer    cells to chemotherapy. J. Biol. Chem. 2002, 277, 5484-5489.-   62. Momand, J.; Wu, H.-H.; Dasgupta, G. MDM2-master regulator of the    p53 tumor suppressor protein. Gene 2000, 242, 15-29.-   63. Motti, M. L.; De Marco, C.; Califano, D.; Fusco, A.;    Viglietto, G. Akt-dependent T198 phosphorylation of cyclin-dependent    kinase inhibitor p27kip1 in breast cancer. Cell Cycle 2004, 3,    1074-1080.-   64. Myers, M. P.; Pass, I.; Batty, I. H.; Van Der Kaay, J.;    Stolarov, J. P.; Hemmings, B. A.; Wigler, M. H.; Downes, C. P.;    Tonks, N. K. The lipid phosphatase activity of PTEN is critical for    its tumor suppressor function. Proc. Natl. Acad. Sci. U.S.A 1998,    95, 13513-13518.-   65. Nagata, Y.; Lan, K.-H.; Zhou, X.; Tan, M.; Esteva, F. J.;    Sahin, A. A.; Nos, K. S.; Li, P.; Monia, B. P.; Nguyen, N. T.;    Hortobagyi, G. N.; Hung, M.-C.; Yu, D. PTEN activation contributes    to tumor inhibition by trastuzumab, and loss of PTEN predicts    trastuzumab resistance in patients. Cancer Cell 2004, 6, 117-127.-   66. Naito, A. T.; Akazawa, H.; Takano, H.; Minamino, T.; Nagai, T.;    Aburatani, H.; Komuro, I. Phosphatidylinositol 3-Kinase-Akt Pathway    Plays a Critical Role in Early Cardiomyogenesis by Regulating    Canonical Wnt Signaling. Circ. Res. 2005, 97, 144-151.-   67. Oda, K.; Stokoe, D.; Taketani, Y.; McCormick, F. High Frequency    of Coexistent Mutations of PIK3CA and PTEN Genes in Endometrial    Carcinoma. Cancer Res. 2005, 65, 10669-10673.-   68. Ogawara, Y.; Kishishita, S.; Obata, T.; Isazawa, Y.; Suzuki, T.;    Tanaka, K.; Masuyama, N.; Gotoh, Y. Akt enhances Mdm2-mediated    ubiquitination and degradation of p53. J. Biol. Chem. 2002, 277,    21843-21850.-   69. Olson, J. M.; Hallahan, A. R. p38 MAP kinase: a convergence    point in cancer therapy. Trends Mol. Med. 2004, 10, 125-129.-   70. Osaki, M.; Oshimura, M.; Ito, H. PI3K-Akt pathway: Its functions    and alterations in human cancer. Apoptosis 2004, 9, 667-676.-   71. Pastorino, J. G.; Tafani, M.; Farber, J. L. Tumor necrosis    factor induces phosphorylation and translocation of BAD through a    phosphatidylinositide-3-0H kinase-dependent pathway. J. Biol. Chem.    1999, 274, 19411-19416.-   72. Pendaries, C.; Tronchere, H.; Plantavid, M.; Payrastre, B.    Phosphoinositide signaling disorders in human diseases. FEBS Lett.    2003, 546, 25-31.-   73. Phillips, W. A.; St. Clair, F.; Munday, A. D.; Thomas, R. J. S.;    Mitchell, C. A. Increased levels of phosphatidylinositol 3-kinase    activity in colorectal tumors. Cancer 1998, 83, 41-47.-   74. Philp, A. J.; Campbell, I. G.; Leet, C.; Vincan, E.; Rockman, S.    P.; Whitehead, R. H.; Thomas, R. J. S.; Phillips, W. A. The    phosphatidylinositol 3′-kinase p85a gene is an oncogene in human    ovarian and colon tumors. Cancer Res. 2001, 61, 7426-7429.-   75. Powis, G.; Bonjouklian, R.; Berggren, M. M.; Gallegos, A.;    Abraham, R.; Ashendel, C.; Zalkow, L.; Matter, W. F.; Dodge, J.    Wortmannin, a potent and selective inhibitor of    phosphatidylinositol-3-kinase. Cancer Res. 1994, 54, 2419-23.-   76. Pu, P.; Kang, C.; Zhang, Z.; Liu, X.; Jiang, H. Downregulation    of PIK3CB by siRNA suppresses malignant glioma cell growth in vitro    and in vivo. Technol. Cancer Res. Treat. 2006, 5, 271-280.-   77. Rahimi, N.; Tremblay, E.; Elliott, B. Phosphatidylinositol    3-kinase activity is required for hepatocyte growth factor-induced    mitogenic signals in epithelial cells. J. Biol. Chem. 1996, 271,    24850-24855.-   78. Roche, S.; Downward, J.; Raynal, P.; Courtneidge, S. A. A    function for phosphatidylinositol 3-kinase b (p85a-p110b) in    fibroblasts during mitogenesis: requirement for insulin- and    lysophosphatidic acid-mediated signal transduction. Mol. Cell. Biol.    1998, 18, 7119-7129.-   79. Roche, S.; Koegl, M.; Courtneidge, S. A. The    phosphatidylinositol 3-kinase a is required for DNA synthesis    induced by some, but not all, growth factors. Proc. Natl. Acad. Sci.    U.S.A 1994, 91, 9185-9.-   80. Romashkova, J. A.; Makarov, S. S. Nf-kB is a target of Akt in    anti-apoptotic PDGF signaling. Nature 1999, 401, 86-90.-   81. Saal, L. H.; Holm, K.; Maurer, M.; Memeo, L.; Su, T.; Wang, X.;    Yu, J. S.; Malmstroem, P.-O.; Mansukhani, M.; Enoksson, J.;    Hibshoosh, H.; Borg, A.; Parsons, R. PIK3CA mutations correlate with    hormone receptors, node metastasis, and ERBB2, and are mutually    exclusive with PTEN loss in human breast carcinoma. Cancer Res.    2005, 65, 2554-2559.-   82. Samuels, Y.; Diaz, L. A., Jr.; Schmidt-Kittler, O.; Cummins, J.    M.; DeLong, L.; Cheong, I.; Rago, C.; Huso, D. L.; Lengauer, C.;    Kinzler, K. W.; Vogelstein, B.; Velculescu, V. E. Mutant PIK3CA    promotes cell growth and invasion of human cancer cells. Cancer Cell    2005, 7, 561-573.-   83. Samuels, Y.; Ericson, K. Oncogenic PI3K and its role in cancer.    Curr. Opin. Oncol. 2006, 18, 77-82.-   84. Samuels, Y.; Wang, Z.; Bardelli, A.; Silliman, N.; Ptak, J.;    Szabo, S.; Yan, H.; Gazdar, A.; Powell, S. M.; Riggins, G. J.;    Willson, J. K. V.; Markowitz, S.; Kinder, K. W.; Vogelstein, B.;    Velculescu, V. E. Brevia: High frequency of mutations of the PIK3Ca    gene in human cancers. Science 2004, 304, 554.-   85. Scheid, M. P.; Marignani, P. A.; Woodgett, J. R. Multiple    phosphoinositide 3-kinase-dependent steps in activation of protein    kinase B. Mol. Cell. Biol. 2002, 22, 6247-6260.-   86. Schultz, R. M.; Merriman, R. L.; Andis, S. L.; Bonjouklian, R.;    Grindey, G. B.; Rutherford, P. G.; Gallegos, A.; Massey, K.;    Powis, G. In vitro and in vivo antitumor activity of the    phosphatidylinositol-3-kinase inhibitor, wortmannin. Anticancer Res.    1995, 15, 1135-9.-   87. Segrelles, C.; Moral, M.; Lara, M. F.; Ruiz, S.; Santos, M.;    Leis, H.; Garcia-Escudero, R.; Martinez-Cruz, A. B.;    Martinez-Palacio, J.; Hernandez, P.; Ballestin, C.; Paramio, J. M.    Molecular determinants of Akt-induced keratinocyte transformation.    Oncogene 2006, 25, 1174-1185.-   88. Sekimoto, T.; Fukumoto, M.; Yoneda, Y. 14-3-3 suppresses the    nuclear localization of threonine 157-phosphorylated p27Kip1.    EMBO J. 2004, 23, 1934-1942.-   89. Semba, S.; Itoh, N.; Ito, M.; Youssef, E. M.; Harada, M.;    Moriya, T.; Kimura, W.; Yamakawa, M. Down-regulation of PIK3CG    catalytic subunit of phosphatidylinositol 3-OH kinase by CpG    hypermethylation in human colorectal carcinoma. Clin. Cancer Res.    2002, 8, 3824-3831.-   90. Shayesteh, L.; Lu, Y.; Kuo, W.-L.; Baldocchi, R.; Godfrey, T.;    Collins, C.; Pinkel, D.; Powell, B.; Mills, G. B.; Gray, J. W.    PIK3CA is implicated as an oncogene in ovarian cancer. Nat. Genet.    1999, 21, 99-102.-   91. Shekar, S. C.; Wu, H.; Fu, Z.; Yip, S.-C.; Nagajyothi;    Cahill, S. M.; Girvin, M. E.; Backer, J. M. Mechanism of    Constitutive Phosphoinositide 3-Kinase Activation by Oncogenic    Mutants of the p85 Regulatory Subunit. J. Biol. Chem. 2005, 280,    27850-27855.-   92. Stahl, J. M.; Cheung, M.; Sharma, A.; Trivedi, N. R.; Shanmugam,    S.; Robertson, G. P. Loss of PTEN Promotes Tumor Development in    Malignant Melanoma. Cancer Res. 2003, 63, 2881-2890.-   93. Stambolic, V.; Suzuki, A.; De La Pompa, J. L.; Brothers, G. M.;    Mirtsos, C.; Sasaki, T.; Ruland, J.; Penninger, J. M.;    Siderovski, D. P.; Mak, T. W. Negative regulation of    PKIVAkt-Dependent cell survival by the tumor suppressor PTEN. Cell    1998, 95, 29-39.-   94. Stauffer, F.; Holzer, P.; Garcia-Echeverria, C. Blocking the    PI3K/PKB pathway in tumor cells. Curr. Med. Chem. Anticancer Agents    2005, 5, 449-462.-   95. Steck, P. A.; Pershouse, M. A.; Jasser, S. A.; Yung, W. K. A.;    Lin, H.; Ligon, A. H.; Langford, L. A.; Baumgard, M. L.; Hattier,    T.; Davis, T.; Frye, C.; Hu, R.; Swedlund, B.; Teng, D. H. F.;    Tavtigian, S. V. Identification of a candidate tumor suppressor    gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple    advanced cancers. Nat. Genet. 1997, 15, 356-362.-   96. Stein, R. C.; Waterfield, M. D. P|3-kinase inhibition: a target    for drug development? Mol. Med. Today 2000, 6, 347-358.-   97. Stephens, L.; Williams, R.; Hawkins, P. Phosphoinositide    3-kinases as drug targets in cancer. Curr. Opin. Pharmacol. 2005, 5,    357-365.-   98. Su, J. D.; Mayo, L. D.; Donner, D. B.; Durden, D. L. PTEN and    Phosphatidylinositol 3′-Kinase Inhibitors Up-Regulate p53 and Block    Tumor-induced Angiogenesis: Evidence for an Effect on the Tumor and    Endothelial Compartment. Cancer Res. 2003, 63, 3585-3592.-   99. Tanaka, M.; Grossman, H. B. In vivo gene therapy of human    bladder cancer with PTEN suppresses tumor growth, downregulates    phosphorylated Akt, and increases sensitivity to doxorubicin. Gene    Ther. 2003, 10, 1636-1642.-   100. Tang, E. D.; Nunez, G.; Barr, F. G.; Guan, K.-L. Negative    regulation of the forkhead transcription factor FKHR by Akt. J.    Biol. Chem. 1999, 274, 16741-16746.-   101. Taylor, V.; Wong, M.; Brandts, C.; Reilly, L.; Dean, N. M.;    Cowsert, L. M.; Moodie, S.; Stokoe, D. 5′ Phospholipid phosphatase    SHIP-2 causes protein kinase B inactivation and cell cycle arrest in    glioblastoma cells. Mol. Cell. Biol. 2000, 20, 6860-6871.-   102. Toker, A. Phosphoinositides and signal transduction. Cell. Mol.    Life Sci. 2002, 59, 761-779.-   103. Traer, C. J.; Foster, F. M.; Abraham, S. M.; Fry, M. J. Are    class II phosphoinositide 3-kinases potential targets for anticancer    therapies? Bull. Cancer (Paris). 2006, 93, E53-8.-   104. Vanhaesebroeck, B.; Leevers, S. J.; Ahmadi, K.; Timms, J.;    Katso, R.; Driscoll, P. C.; Woscholski, R.; Parker, P. J.;    Waterfield, M. D. Synthesis and function of 3-phosphorylated    inositol lipids. Annu. Rev. Biochem. 2001, 70, 535-602.-   105. Vanhaesebroeck, B.; Waterfield, M. D. Signaling by Distinct    Classes of Phosphoinositide 3-Kinases. Exp. Cell Res. 1999, 253,    239-254.-   106. Vivanco, I.; Sawyers, C. L. The phosphatidylinositol    3-Kinase-AKT pathway in human cancer. Nat. Rev. Cancer 2002, 2,    489-501.-   107. Wang, Y.; Helland, A.; Holm, R.; Kristensen Gunnar, B.;    Borresen-Dale, A.-L. PIK3CA mutations in advanced ovarian    carcinomas. Hum. Mutat. 2005, 25, 322.-   108. West, K. A.; Castillo, S. S.; Dennis, P. A. Activation of the    PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist.    Update. 2002, 5, 234-48.-   109. Whyte, D. B.; Holbeck, S. L. Correlation of PIK3Ca mutations    with gene expression and drug sensitivity in NCI-60 cell lines.    Biochem. Biophys. Res. Commun. 2006, 340, 469-475.-   110. Wilker, E.; Lu, J.; Rho, O.; Carbajal, S.; Beltran, L.;    DiGiovanni, J. Role of PI3K/Akt signaling in insulin-like growth    factor-1 (IGF-1) skin tumor promotion. Mol. Carcinog. 2005, 44,    137-145.-   111. Workman, P. Inhibiting the phosphoinositide 3-kinase pathway    for cancer treatment. Biochem. Soc. Trans. 2004, 32, 393-396.-   112. Wu, G.; Xing, M.; Mambo, E.; Huang, X.; Liu, J.; Guo, Z.;    Chatterjee, A.; Goldenberg, D.; GoIlin, S. M.; Sukumar, S.; Trink,    B.; Sidransky, D. Somatic mutation and gain of copy number of PIK3CA    in human breast cancer. Breast Cancer Res. 2005, 7, R609-R616.-   113. Wymann, M. P.; Sozzani, S.; Altruda, F.; Mantovani, A.;    Hirsch, E. Lipids on the move: phosphoinositide 3-kinases in    leukocyte function. Immunol. Today 2000, 21, 260-264.-   114. Yap, D. B.; Hsieh, J. K.; Lu, X. Mdm2 inhibits the apoptotic    function of p53 mainly by targeting it for degradation. J. Biol.    Chem. 2000, 275, 37296-302.-   115. Yuan, Z.-q.; Feldman, R. I.; Sussman, G. E.; Coppola, D.;    Nicosia, S. V.; Cheng, J. Q. AKT2 Inhibition of Cisplatin-induced    JNK/p38 and Bax Activation by Phosphorylation of ASK1: Implication    of AKT2 in Chemoresistance. J. Biol. Chem. 2003, 278, 23432-23440.-   116. Zhao, H.; Dupont, J.; Yakar, S.; Karas, M.; LeRoith, D. PTEN    inhibits cell proliferation and induces apoptosis by downregulating    cell surface IGF-IR expression in prostate cancer cells. Oncogene    2004, 23, 786-794.-   117. Zhao, J. J.; Cheng, H.; Jia, S.; Wang, L.; Gjoerup, O. V.;    Mikami, A.; Roberts, T. M. The p110α isoform of PI3K is essential    for proper growth factor signaling and oncogenic transformation.    Proc. Natl. Acad. Sci. U.S.A 2006, 103, 16296-300.-   118. Zhou, B. P.; Liao, Y.; Xia, W.; Spohn, B.; Lee, M.-H.; Hung,    M.-C. Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced    phosphorylation in HER-2/neu-oyerexpressing cells. Nat. Cell Biol.    2001, 3, 245-252.

REFERENCES

-   1A. Kenkre V P, Kahl B S. Curr Hematol Malig Rep 2012; 7: 216-220-   2A. Iyengar S et al. Blood 2013; [Epub ahead of print]-   3A. Liu N et al. Poster 4476 presented at the 101st Annual Meeting    of the American Association for Cancer Research, Washington D.C.,    USA, Apr. 17-21, 2010-   4A. Ziegelbauer K et al. Br J. Pharmacol 2005; 145: 178-192-   5A. Puri K D, Gold M R. Front Immunol 2012; 3: 256-   6A. Patnaik A et al. Poster 3704 presented at the 54th ASH Annual    meeting and exposition, Atlanta, Ga., USA, Dec. 8-11, 2012-   7A. Chou T C. Pharmacol Rev 2006; 58: 621-681

1. A method for the treatment of non-Hodgkin's lymphoma (NHL) comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a 2,3-dihydroimidazo[1,2-c]quinazoline compound of formula:

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, in which: R¹ represents—(CH₂)_(n)—(CHR⁴)—(CH₂)_(m)—N(R⁵)(R^(5′)); R² represents a heteroaryloptionally substituted with 1, 2 or 3 R⁶ groups; R³ represents alkyl orcycloalkyl; R⁴ represents hydrogen, hydroxy or alkoxy; R⁵ and R^(5′) maybe the same or different and are independently, hydrogen, alkyl,cycloalkylalklyl, or alkoxyalkyl or R⁵ and R^(5′) may be taken togetherwith the nitrogen atom to which they are bound to form a 3-7 memberednitrogen containing heterocyclic ring optionally containing at least oneadditional heteroatom selected from oxygen, nitrogen or sulfur and whichmay be optionally substituted with 1 or more R^(6′) groups, or R⁴ and R⁵may be taken together with the atoms to which they are bound to form a5-6 membered nitrogen containing heterocyclic ring optionally containing1 or more nitrogen, oxygen or sulfur atoms and which may be optionallysubstituted with 1 or more R^(6′) groups; each occurrence of R⁶ may bethe same or different and is independently halogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalklyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclic ring, heterocyclylalkyl, alkyl-OR⁷,alkyl-SR′, alkyl-N(R⁷)(e), alkyl-COR′, —CN, —COOR⁷, —CON(R⁷)(R^(7′)),—OR′, —SR′, —N(R⁷)(R^(7′)), or NR⁷COR⁷ each of which may be optionallysubstituted with 1 or more R⁸ groups; each occurrence of R^(6′) may bethe same or different and is independently alkyl, cycloalkylalklyl, oralkyl-OR⁷; each occurrence of R⁷ and R^(7′) may be the same or differentand is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl, heteroaryl,heterocyclic ring, heterocyclylalkyl, or heteroarylalkyl; eachoccurrence of R⁸ is independently nitro, hydroxy, cyano, formyl, acetyl,halogen, amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl, heteroaryl,heterocyclic ring, heterocyclylalkyl, or heteroarylalkyl; and n is aninteger from 1-4 and m is an integer from 0-4 with the proviso that whenR⁴ and R⁵ are taken together with the atoms to which they are bound toform a 3-7 membered nitrogen containing ring, n+m≧4.
 2. The methodaccording to claim 1, wherein R⁴ is hydroxy.
 3. The method according toclaim 1, wherein R⁴ and R⁵ are taken together with the atoms to whichthey are bound to form a 5-6 membered nitrogen containing heterocyclicring optionally containing 1 or more nitrogen, oxygen or sulfur atomsand which may be optionally substituted with 1 or more R^(6′) groups. 4.The method according to claim 1, wherein R² is pyridine, pyridazine,pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan or thiophene,optionally substituted with 1, 2 or 3 R⁶ groups.
 5. The method accordingto claim 1, wherein said compound of formula (I) has the formula:

where R² is as defined in claim
 1. 6. The method according to claim 5,wherein R² is pyridine, pyridazine, pyrimidine, pyrazine, pyrole,oxazole, thiazole, furan or thiophene, optionally substituted with 1, 2or 3 R⁶ groups.
 7. The method according to claim 1, wherein saidcompound is selected fromN-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-2,4-dimethyl-1,3-thiazole-5-carboxamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-thiazole-5-carboxamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]isonicotinamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-methyl-1,3-thiazole-5-carboxamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-propylpyrimidine-5-carboxamide;N-{8-[2-(4-ethylmorpholin-2-yl)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide1-oxide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(2-pyrrolidin-1-ylethyl)nicotinamide;6-(cyclopentylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[8-(2-hydroxy-3-morpholin-4-ylpropoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-{7-methoxy-8-[3-(3-methylmorpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-(8-{2-[4-(cyclobutylmethyl)morpholin-2-yl]ethoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-(7-methoxy-8-{2-[4-(2-methoxyethyl)morpholin-2-yl]ethoxy}-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-{8-[(4-ethylmorpholin-2-yl)methoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-(7-methoxy-8-{[4-(2-methoxyethyl)morpholin-2-yl]methoxy}-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-{7-methoxy-8-[(4-methylmorpholin-2-yl)methoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-4-carboxamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-4-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-methyl-1H-imidazole-4-carboxamide;rel-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;rel-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-6-methylnicotinamide;rel-6-acetamido-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-methyl-1H-imidazole-5-carboxamide;6-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-methylnicotinamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-methylpyrimidine-5-carboxamide;6-amino-5-bromo-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-oxazole-5-carboxamide;N-[7-methoxy-8-(morpholin-2-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;2-{[2-(dimethylamino)ethyl]amino}-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;2-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-1,3-thiazole-5-carboxamide;rel-2-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;rel-6-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;2-[(2-hydroxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-[(3-methoxypropyl)amino]pyrimidine-5-carboxamide;2-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-[(3-morpholin-4-ylpropyl)amino]pyrimidine-5-carboxamide;2-[(2-methoxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;2-{[2-(dimethylamino)ethyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;6-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-pyrrolidin-1-ylpyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-morpholin-4-ylpyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-piperazin-1-ylnicotinamidehydrochloride;6-[(3S)-3-aminopyrrolidin-1-yl]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamidehydrochloride hydrate;6-[(3R)-3-aminopyrrolidin-1-yl]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamidehydrochloride;6-[(4-fluorobenzyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;6-[(2-furylmethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;6-[(2-methoxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(1H-pyrrol-1-yl)nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-morpholin-4-ylnicotinamide;N-{7-methoxy-8-[3-(methylamino)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;6-[(2,2-dimethylpropanoyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;6-[(cyclopropylcarbonyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamideN-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(2,2,2-trifluoroethoxy)nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(trifluoromethyl)nicotinamide;6-(isobutyrylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-{7-methoxy-8-[3-(4-methylpiperazin-1-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-{[(methylamino)carbonyl]amino}-1,3-thiazole-4-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-{[(methylamino)carbonyl]amino}nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(methylamino)-1,3-thiazole-4-carboxamide;N-[7-methoxy-8-(2-morpholin-4-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-2,4-dimethyl-1,3-thiazole-5-carboxamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-6-methylnicotinamide;6-{[(isopropylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-pyrrolidin-1-ylnicotinamide;6-(dimethylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-piperidin-1-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(2-pyrrolidin-1-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(2-piperidin-1-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;6-{[(ethylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;6-fluoro-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-oxazole-4-carboxamide;2-(ethylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-thiazole-4-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrazine-2-carboxamide;N-[8-(2-aminoethoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;6-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]isonicotinamide;N-{8-[3-(diethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-{8-[2-(diisopropylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-{8-[2-(diethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(methylamino)pyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(methylthio)pyrimidine-5-carboxamide;N-[8-(3-aminopropoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamidetrifluoroacetate;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]thiophene-2-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2,4-dimethyl-1,3-thiazole-5-carboxamide;2-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-3-furamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]thiophene-3-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-methyl-1,3-thiazole-4-carboxamide;6-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;5-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-methylnicotinamide;6-(acetylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;andN-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamideor a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof.
 8. The method according to claim 1, wherein said compound is2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide.9. The method according to claim 1, wherein said compound is2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamidedihydrochloride.
 10. A pharmaceutical combination of: a) a2,3-dihydroimidazo[1,2-c]quinazoline compound according to claim 1, or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof; and b) one or more additional active agents selected from thegroup consisting of: PI3Kδ-selective inhibitor GS-1101, BTK inhibitoribrutinib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766(RDEA-119)).
 11. The pharmaceutical combination according to claim 10,wherein said 2,3-dihydroimidazo[1,2-c]quinazoline compound is2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide.12. The pharmaceutical combination according to claim 10, wherein said2,3-dihydroimidazo[1,2-c]quinazoline compound is or2,3-dihydroimidazo[1,2-c]quinazoline compound is2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamidedihydrochloride.
 13. The pharmaceutical combination according to claim11, wherein said additional active agent is PI3Kδ-selective inhibitorGS-1101.
 14. The pharmaceutical combination according to claim 11,wherein said additional active agent is BTK inhibitor ibrutinib.
 15. Thepharmaceutical combination according to claim 11, wherein saidadditional active agent is IKK inhibitor BAY Compound B.
 16. Thepharmaceutical combination according to claim 11, wherein saidadditional active agent is REFAMETINIB (BAY 86-9766 (RDEA-119)).
 17. Apharmaceutical composition which comprises a combination of: a) a2,3-dihydroimidazo[1,2-c]quinazoline compound according to claim 1, or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof; and b) one or more additional active agents selected from thegroup consisting of: PI3Kδ-selective inhibitor GS-1101, BTK inhibitoribrutinib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766(RDEA-119)).
 18. A method for the treatment of non-Hodgkin's lymphoma(NHL) comprising administering to a patient in need thereof atherapeutically effective amount of a combination of: a) a2,3-dihydroimidazo[1,2-c]quinazoline compound according to claim 1, or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof; and b) one or more additional active agents selected from thegroup consisting of: PI3Kδ-selective inhibitor GS-1101, BTK inhibitoribrutinib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766(RDEA-119)); or a pharmaceutical composition containing such acombination.
 19. (canceled)
 20. (canceled)
 21. The method according toclaim 1, wherein the non-Hodgkin's lymphoma (NHL) is selected from 1stline, 2nd line, relapsed, refractory, indolent or aggressivenon-Hodgkin's lymphoma (NHL); follicular lymphoma (FL); chroniclymphocytic leukaemia (CLL); marginal zone lymphoma (MZL); diffuse largeB-cell lymphoma (DLBCL); mantle cell lymphoma (MCL); transformedlymphoma (TL); and peripheral T-cell lymphoma (PTCL).
 22. The methodaccording to claim 1, wherein said compound is selected from:N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-methylnicotinamide;5-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2,4-dimethyl-1,3-thiazole-5-carboxamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;6-{[(isopropylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-2,4-dimethyl-1,3-thiazole-5-carboxamide;N-[7-methoxy-8-(2-morpholin-4-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;rel-6-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;rel-2-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;andN-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof.
 23. The pharmaceutical combination according to claim 12,wherein said additional active agent is PI3Kδ-selective inhibitorGS-1101.
 24. The pharmaceutical combination according to claim 12,wherein said additional active agent is BTK inhibitor ibrutinib.
 25. Thepharmaceutical combination according to claim 12, wherein saidadditional active agent is IKK inhibitor BAY Compound B.
 26. Thepharmaceutical combination according to claim 12, wherein saidadditional active agent is REFAMETINIB (BAY 86-9766 (RDEA-119)).
 27. Themethod according to claim 18, wherein the non-Hodgkin's lymphoma (NHL)is selected from 1st line, 2nd line, relapsed, refractory, indolent oraggressive non-Hodgkin's lymphoma (NHL); follicular lymphoma (FL);chronic lymphocytic leukaemia (CLL); marginal zone lymphoma (MZL);diffuse large B-cell lymphoma (DLBCL); mantle cell lymphoma (MCL);transformed lymphoma (TL); and peripheral T-cell lymphoma (PTCL).